(ER+, ER- pr-oxidation, hot flash, mTor inhib, EGFR inhib, PI3K/Akt, chemo synergy: w/5FU and Mitoxantrone in ER+, w/Adriamycin, Taxotere, Cisplatin in ER-, w/Herceptin, synergy with green tea (ER+/-), curcumin, flaxseed (Er+), selenium, crosses BBB, off-label scripts (eg gamma secretase inhib) to kill CSC, resistance reversal strategies, potential agonist, Tamoxitest ERRgamma & menin to predict metabolism/benefit, possibly helped by aspirin)
Tamoxifen: the drug that came in from the cold
(PDF attached at bottom of section)
http://www.nature.com/bjc/journal/v1.../6605231a.html
L Hughes-Davies1, C Caldas2,3 and GC Wishart*,1,3
1Cambridge Breast Unit, Addenbrooke’s Hospital, Hills Road, Cambridge, UK; 2Department of Oncology, University of Cambridge, and Functional Breast
Cancer Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; 3NIHR
Cambridge Biomedical Research Centre, Cambridge, UK
Despite the perception of many oncologists that tamoxifen is an inferior drug, and should be substituted by an aromatase inhibitor in
post-menopausal women, the current evidence strongly supports the view that AIs should be used 2–3 years after tamoxifen to achieve the maximal overall survival (OS) advantage.
British Journal of Cancer (2009) 101, 875–878. doi:10.1038/sj.bjc.6605231 www.bjcancer.com
Published online 11 August 2009
& 2009 Cancer Research UK
J Cancer Res Clin Oncol. 2009 Jun;135(6):807-13. Epub 2008 Nov 26. HER2 overexpression and activation, and tamoxifen efficacy in receptor-positive early breast cancer.
Singer CF, Gschwantler-Kaulich D, Fink-Retter A, Pfeiler G, Walter I, Hudelist G, Helmy S, Spiess AC, Lamm W, Kubista E.
Division of Special Gynaecology, Vienna Medical University, Vienna, Austria. christian.singer@meduniwien.ac.at
OBJECTIVES: Tamoxifen is a partial ER antagonist that is highly effective in the treatment of receptor positive breast cancer. It significantly reduces recurrence and improves survival in both pre- and postmenopausal women. Unfortunately, many ER+ positive tumors progress despite tamoxifen treatment and until now, no possibility exists to prospectively identify tamoxifen-resistant tumors. It has been suggested that that in HER2 over-expressing tumors, cross-talk via activated HER2 receptors is a key mechanisms by which tumors become tamoxifen-resistant. METHODS: We have therefore used immunohistochemistry to analyze the expression of HER2 and activated ptyr-1248 HER2 in 408 women of ER+, early breast cancer who had received at least 2 years of adjuvant tamoxifen. We then analyzed possible associations between HER2 and pHER2 expression, and prognostic parameters, and evaluated the effect of HER2 expression and survival. RESULTS: With HER2 being positive in 12 of 208 (2.9%) of ER+ positive tumors, HER2 overexpression was found to be considerably less common in ER+ tumors than what has been thought previously. The majority of HER2 overexpressing tumors, however, also expressed the activated receptor form (r = 0.664; P < 0.0001). Both HER2 and pHER2 are moderately correlated with Grading (r = 0.138; P = 0.0052 and r = 0.118; P = 0.0241, respectively) and nodal involvement (r = 0.163; P = 0.0018 and r = 0.134; P = 0.016, respectively), but neither HER2 nor its activated form are significant predictors of RFS, DFS, or OS. CONCLUSIONS: Taken together, we have demonstrated that in ER+ breast cancer, the HER2 receptor is commonly activated, but its low prevalence in ER+ tumors does not render it a useful prognostic parameter in tamoxifen-treated patients.
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There is now growing evidence that in tumors with active growth factor receptor signaling (e.g., HER2 amplification), tamoxifen may lose its estrogen antagonist activity and may acquire more agonist-like activity, resulting in tumor growth stimulation (Osborne et al. 2005). Massarweh et al. have recently demonstrated in an in vivo model of MCF-7 breast cancer cells that EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. Their study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress HER2 (Massarweh et al. 2008). The same group also showed that tamoxifen behaves as an estrogen agonist in breast cancer cells that express high levels of AIB1 and HER2, resulting in de novo resistance. Antibody-mediated inhibition of the HER pathway blocked receptor cross-talk, re-established co-repressor complexes with tamoxifen-bound ER on target gene promoters, eliminated tamoxifen’s agonist eVects, and restored its anti-tumor activity both in vitro and in vivo (Shou et al. 2004).
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Taken together, there is now compelling experimental and clinical evidence suggesting that HER signaling pathways, when overexpressed and/or hyperactivated, can modulate both activities of ER, resulting in endocrine resistance. The signal transduction receptors and signaling molecules may therefore serve as both predictive markers and novel therapeutic targets to circumvent endocrine resistance (SchiV et al. 2005)
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While in our samples, HER2 overexpression was only detected in 3% of ER-positive tumors, we found activated (p)HER2 in 42% of HER2 positive (3+) tumors, thus indicating that when HER2 is overexpressed in ER-positive tumors, it is commonly activated. This is somewhat similar to our previous finnding of approximately 31% of the HER2 overexpressing tumors being activated.
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In fact, in four tumors that did not overexpress HER2, pHER2 was nevertheless found to be activated.
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The HER2 activity seen in the majority of our HER2 overexpressing breast tumors can therefore be seen as an attempt to down-regulate ER expression in order to render a tumor receptor negative and independent of estrogenic growth stimulation. This hypothesis is further supported by recent observations in a xenograft model of ER+, HER2-overexpressing breast cancer (Massarweh et al. 2006).
Estrogen-dependent HER2-transfected MCF-7 xenografts rapidly grow in nude mice in the presence of estrogen but quickly regress following estrogen withdrawal. However, after approximately 3 months of growth arrest, the tumors resume growth which is now estrogen independent.
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/the low prevalence of HER2 overexpression in ER+ tumors precludes an evaluation of the eVect of receptor overexpression and/or activation on clinical parameters such as DFS or OS. We therefore conclude that, despite convincing pre-clinical evidence, Her2 overexpression is not a useful prognostic parameter in tamoxifen-treated patients.
Targeting notch signaling and estrogen receptor pathways in human breast cancer stem cells(TAM + Gamma Secretase inhibitor)
N. S. Luraguiz, T. Yong, H. Yin and A. Sun Feist Weiller Cancer Center, LSUHSC, Shreveport, LA 22066 Background: Breast cancer stem cells have been identified asESA+CD44+CD24-Lin- cells, which may account for disease relapseand metastasis. Deregulation in stem cell self-renewal pathwayssuch as Notch, Wnt and Hedgehog signaling have been implicatedin mammary transformation. In humans, high levels of Notch1are associated with reduced patient survival. Inhibition ofNotch signaling has been proposed as a potential strategy intreating breast cancer. Tamoxifen, a modulator of estrogen receptor(ER), is currently used for the treatment of both early andadvanced ER+ breast cancer. It is unclear whether ER+ breastcancers originate from ER+ or ER- mammary stem/progenitor cells.Here, we investigate the molecular mechanisms of Notch signalingand ER interaction in breast cancer stem cells, and evaluateNotch inhibition and estrogen antagonist in targeting breastcancer stem cells. Methods: CD44+CD24- breast cancer stem cellsare isolated by flow cytometry sorting of (1) human breast cancercell line MDA-MB-231, (2) primary cells from invasive breastcancer lesions and (3) primary cells from benign breast tissues.Real-time PCR is performed to determine the expression of stemcell genes including genes in Notch pathway. IHC is performedto determine the ER and PR status of the cells. Stem like andnon-stem like cells are treated with GSI (a Notch inhibitor)and tamoxifen. The effects of the treatments on cell proliferationand apoptosis are determined by BrdU and Tunnel Assays. Resultsand Conclusion:induced apoptosis in ER- MDA-MB-231 cells. Tamoxifen alone hadsubstantial killing effects on ER+ MCF7 cells, but enhancedkilling in both cell types were observed when treatments werecombined. Stem like, non stem-like and unsorted cells were treatedwith GSI, tamoxifen and combination of GSI and tamoxifen. Previously we have shown that GSI alone effectively Proliferationwas determined at 24 and 72 hours of treatment by BrdU assay.Stem-like cells exhibited significant sensitivity to GSI killingIn addition, an enhanced effect was observed when GSI was combinedwith tamoxifen, suggesting that chemotherapy that targets bothNotch signaling and estrogen receptor pathways in breast cancerstem cells may be an effective strategy in treating breast cancer.
Hot Flash=efficacy issue (Now and Then):
Breast Cancer Res Treat.2009 Oct;117(3):571-5. Epub 2009 Jan 20. Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort.
Lynn Henry N, Rae JM, Li L, Azzouz F, Skaar TC, Desta Z, Sikora MJ, Philips S, Nguyen AT, Storniolo AM, Hayes DF, Flockhart DA, Stearns V; Consortium on Breast Cancer Pharmacogenomics Investigators.
Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA, norahh@med.umich.edu. Women with reduced CYP2D6 activity have low endoxifen concentrations and likely worse long term benefits from tamoxifen. We investigated the association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. We collected hot flash frequency and severity data over 12 months from 297 women initiating tamoxifen. We performed CYP2D6 genotyping using the AmpliChip CYP450 test and correlated inherited genetic polymorphisms in CYP2D6 and tamoxifen-induced hot flashes. Intermediate metabolizers had greater mean hot flash scores after 4 months of tamoxifen therapy (44.3) compared to poor metabolizers (20.6, P = 0.038) or extensive metabolizers (26.9, P = 0.011). At 4 months, we observed a trend toward fewer severe hot flashes in poor metabolizers compared to intermediate plus extensive metabolizers (P = 0.062). CYP2D6 activity may be a modest predictive factor for tamoxifen-induced hot flashes. The presence or absence of hot flashes should not be used to determine tamoxifen's efficacy.
PMID: 19153830 [PubMed - indexed for MEDLINE]
2008:
Breast Cancer Res Treat. 2008 Apr;108(3):421-6. Epub 2007 May 31. Tamoxifen, hot flashes and recurrence in breast cancer.
Cancer Prevention and Control Program, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093-0901, USA.
We utilized data from the comparison group of the Women's Healthy Eating and Living randomized trial to investigate an "a priori" hypothesis suggested by CYP2D6 studies that hot flashes may be an independent predictor of tamoxifen efficacy. A total of 1551 women with early stage breast cancer were enrolled and randomized to the comparison group of the WHEL multi-institutional trial between 1995 and 2000. Their primary breast cancer diagnoses were between 1991 and 2000. At study entry, 864 (56%) of these women were taking tamoxifen, and hot flashes were reported by 674 (78%). After 7.3 years of follow-up, 127 of those who took tamoxifen at baseline had a confirmed breast cancer recurrence. Women who reported hot flashes at baseline were less likely to develop recurrent breast cancer than those who did not report hot flashes (12.9% vs 21%, P = 0.01). Hot flashes were a stronger predictor of breast cancer specific outcome than age, hormone receptor status, or even the difference in the stage of the cancer at diagnosis (Stage I versus Stage II). These findings suggest an association between side effects, efficacy, and tamoxifen metabolism. The strength of this finding suggests that further study of the relationship between hot flashes and breast cancer progression is warranted. Additional work is warranted to clarify the mechanism of hot flashes in this setting.
PMID: 17541741 [PubMed - indexed for MEDLINE]
2005:
J Clin Oncol. 2005 Dec 20;23(36):9312-8. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes.
PURPOSE: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. METHODS: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. RESULTS: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. CONCLUSION: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.
PMID: 16361630 [PubMed - indexed for MEDLINE]
Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells+ Author Affiliations
Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland
Matthias A. Hediger, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland CH-3012. Phone: 41-31-631-4129; Fax: 41-31-631-3410. E-mail: matthias.hediger@mci.unibe.ch
Note: K.A. Bolanz and G.G. Kovacs contributed equally to this work.
Abstract
The epithelial calcium channel TRPV6 is upregulated in breast carcinoma compared with normal mammary gland tissue. The selective estrogen receptor modulator tamoxifen is widely used in breast cancer therapy. Previously, we showed that tamoxifen inhibits calcium uptake in TRPV6-transfected Xenopus oocytes. In this study, we examined the effect of tamoxifen on TRPV6 function and intracellular calcium homeostasis in MCF-7 breast cancer cells transiently transfected with EYFP-C1-TRPV6. TRPV6 activity was measured with fluorescence microscopy using Fura-2. The basal calcium level was higher in transfected cells compared with nontransfected cells in calcium-containing solution but not in nominally calcium-free buffer. Basal influxes of calcium and barium were also increased. In transfected cells, 10 μmol/L tamoxifen reduced the basal intracellular calcium concentration to the basal calcium level of nontransfected cells. Tamoxifen decreased the transport rates of calcium and barium in transfected cells by 50%. This inhibitory effect was not blocked by the estrogen receptor antagonist, ICI 182,720. Similarly, a tamoxifen-induced inhibitory effect was also observed in MDA-MB-231 estrogen receptor–negative cells. The effect of tamoxifen was completely blocked by activation of protein kinase C. Inhibiting protein kinase C with calphostin C decreased TRPV6 activity but did not alter the effect of tamoxifen. These findings illustrate how tamoxifen might be effective in estrogen receptor–negative breast carcinomas and suggest that the therapeutic effect of tamoxifen and protein kinase C inhibitors used in breast cancer therapy might involve TRPV6-mediated calcium entry. This study highlights a possible role of TRPV6 as therapeutic target in breast cancer therapy. (Mol Cancer Res 2009;7(12):2000–10)
Exp Cell Res. 2009 Jul 15;315(12):2022-32. Epub 2009 Apr 22. Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways.
Matsuoka H, Tsubaki M, Yamazoe Y, Ogaki M, Satou T, Itoh T, Kusunoki T, Nishida S.
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan.
In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities of matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKCalpha and PKCdelta phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.
PMID: 19393235 [PubMed - indexed for MEDLINE]
Anticancer Drugs. 2009 Sep;20(8):723-35. The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells.
Yde CW, Clausen MP, Bennetzen MV, Lykkesfeldt AE, Mouritsen OG, Guerra B.
Department of Biochemistry and Molecular Biology, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Tamoxifen resistance is a major clinical problem in the treatment of estrogen receptor alpha-positive breast tumors. It is, at present, unclear what exactly causes tamoxifen resistance. For decades, chlorpromazine has been used for treating psychotic diseases, such as schizophrenia. However, the compound is now also recognized as a multitargeting drug with diverse potential applications, for example, it has antiproliferative properties and it can reverse resistance toward antibiotics in bacteria. Furthermore, chlorpromazine can reverse multidrug resistance caused by overexpression of P-glycoprotein in cancer cells. In this study, we have investigated the effect of chlorpromazine on tamoxifen response of human breast cancer cells. We found that chlorpromazine worked synergistically together with tamoxifen with respect to reduction of cell growth and metabolic activity, both in the antiestrogen-sensitive breast cancer cell line, MCF-7, and in a tamoxifen-resistant cell line, established from the MCF-7 cells. Tamoxifen-sensitive and tamoxifen-resistant cells were killed equally well by combined treatment with chlorpromazine and tamoxifen. This synergistic effect could be prevented by addition of estrogen, suggesting that chlorpromazine enhances the effect of tamoxifen through an estrogen receptor-mediated mechanism. To investigate this putative mechanism, we applied biophysical techniques to simple model membranes in the form of unilamellar liposomes of well-defined composition and found that chlorpromazine interacts strongly with lipid bilayers of different composition leading to increased permeability. This implies that chlorpromazine can change influx properties of membranes hence suggesting that chlorpromazine may be a promising chemosensitizing compound for enhancing the cytotoxic effect of tamoxifen.
PMID: 19584708 [PubMed - indexed for MEDLINE]
[3098] Curcumin Modulates Tamoxifen Response in Resistant Breast Cancer Cells.
De Gasperi MJ, Cavazos D, deGraffenried LA University of Texas at Austin, Austin, TX
Despite significant improvement in both detection and treatment, breast cancer remains the second leading cause of cancer deaths for women in the United States. Tamoxifen is the most commonly used treatment for estrogen receptor positive (ER+) breast carcinoma, yet up to 50% of patients with metastatic disease present with de novo resistance to tamoxifen, and almost all patients will eventually become resistant to tamoxifen treatment. The mechanism(s) for this resistance appear to be largely dependent upon activation of growth factor signaling pathways. Aberrant activation of the PI3K/Akt and MAPK pathways and their cross talk with both the genomic and nongenomic activity of the ER is implicated in tamoxifen resistance. Breast cancer cell lines with constitutively activated Akt are characterized by high levels of the pro-survival transcription factor Nuclear Factor kappa B (NF-kB), estrogen-independent growth, and resistance to tamoxifen treatment. Studies have shown that curcumin, a polyphenol derived from the rhizome of the perennial herb Curcuma longa, is able to inhibit the activation of NF-kB, which is implicated as one mechanism by which breast cancer cells become resistant to tamoxifen treatment. Previous studies in our laboratory have demonstrated that inhibition of NF-kB is sufficient to sensitize MCF-7 cells that have constitutively activated Akt and elevated NF-kB levels to tamoxifen treatment. However, clinical NF-kB inhibitors such as Velcade generally involve suppression of the proteosome, leading to severe toxicities. Therefore, identification of alternative approaches for suppressing NF-kB activity in the absence of toxicity could prove beneficial for enhancing response to tamoxifen. In the present study, we assessed the efficacy of curcumin at inhibiting breast cancer cell proliferation and survival both as a single agent and in combination with tamoxifen in MCF-7 cells that expressed both “normal” levels of Akt (Control) activity as well as those that expressed the constitutively active form of Akt (myrAkt). As has been previously reported, curcumin treatment inhibited survival and proliferation in the Control MCF-7 cells, but importantly curcumin was also able to suppress survival and proliferation in the myrAKT MCF-7 cells. Curcumin and tamoxifen co-treatment was found to synergistically inhibit survival in myrAKT MCF-7 cells. These findings demonstrate that curcumin can sensitize myrAKT MCF-7 cells to tamoxifen treatment. This preliminary data suggests that the combination of natural NF-kB inhibitors such as curcumin with tamoxifen may be a viable strategy to either prevent tamoxifen resistant disease or to re-sensitize refractory disease to tamoxifen treatment.
Friday, December 11, 2009 5:30 PM
Poster Session 3: Treatment: Alternative Therapies (5:30 PM-7:30 PM)
Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-α, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.
"Although we had access to only a single patient's tissues demonstrating tamoxifen's agonistic properties in resistant disease, several references spanning from the 1970s to the 1990s have documented that tamoxifen-induced increase in tumor growth is clinically relevant and not isolated to in vitro models and rare cases (4–8). All of these studies demonstrated this phenomenon by showing tumor regression upon tamoxifen withdrawal, with the largest series of 61 patients demonstrating an overall response rate of 8%, including one patient who achieved a complete remission (8). This response rate rises to 18% if one considers only those women who initially had demonstrable benefit from tamoxifen."
....
Although other molecular mechanisms have been shown to directly or indirectly phosphorylate ER and lead to tamoxifen-induced growth of breast cancer in vitro, this report demonstrates that loss of p21 can reverse the cellular response to this SERM from antagonistic to agonistic. It is possible and likely that other mechanisms of tamoxifen resistance exist. However, the cumulative data from these studies point to aberrant phosphorylation of ER serine residues as a final common pathway leading to tamoxifen resistance/stimulated growth. Therefore, the development of therapies directed against phosphorylated ER may prove beneficial in the prevention and treatment of tamoxifen resistance.
Estrogen Receptor-Alpha, Breast Cancer Patients and Tamoxifen Response
ScienceDaily (Nov. 25, 2009)
Researchers have found evidence of a statistically significant survival benefit from adjuvant tamoxifen among patients whose estrogen receptor (ER)-positive tumors had high levels of phosphorylation of ER-alpha; at serine-118 (ER-alpha S118-P), according to a brief communication published online November 25 in the Journal of the National Cancer Institute. Approximately 50% of breast carcinomas are resistant to tamoxifen. Preclinical studies have shown that ER-alpha S118-P is required for response to tamoxifen.
Göran Landberg, M.D., Ph.D., of the Breakthrough Breast Cancer Research Unit, School of Cancer, Enabling Sciences and Technology at the University of Manchester, and colleagues evaluated data from 239 premenopausal patients with breast cancer who participated in a randomized trial of 2 years of adjuvant tamoxifen treatment vs. no systemic treatment. The association between recurrence-free survival and ER-alpha S118-P expression in tumor tissue was investigated. Researchers found evidence of a statistically significant recurrence-free survival benefit from adjuvant tamoxifen, compared with no systemic treatment, among patients whose tumors had high ER-alpha S118-P expression (23.7 vs. 72.2 recurrences per 1000 person-years) but not among patients whose tumors had low expression (51.0 vs. 57.0 recurrences per 1000 person-years). ER-alpha S118-P was not associated with a benefit among untreated patients.
"Our study highlights the importance of assessing the functionality of a drug target," the authors write. "Future studies are necessary to evaluate whether ER-alpha S118-P expression is associated with tamoxifen response among post-menopausal patients."
Int J Oncol. 2007 Feb;30(2):509-20. Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer.
Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, Jordan VC.
Department of Pathology, Oncology Institute, Cardinal Bernadin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
Tamoxifen resistance is common for estrogen receptor alpha (ERalpha) positive breast cancer. Second-line therapies include aromatase inhibitors or fulvestrant. We have shown previously that fulvestrant reversed 17beta-estradiol-induced tumor regression of tamoxifen-stimulated MCF-7 xenografts (MCF-7TAMLT) treated for >5 years with tamoxifen in athymic mice and paradoxically stimulated growth. We investigated mechanisms responsible for growth by fulvestrant in the presence of physiologic estradiol and therapeutic strategies in vivo. The results demonstrated that only estradiol increased expression of the estrogen-responsive genes, c-myc, igf-1, cathepsin D, and pS2 mRNAs, in MCF-7E2 and MCF-7TAMLT tumors. Tamoxifen or fulvestrant decreased the estradiol-induced increase of these mRNAs in both tumor models. However, tyrosine-phosphorylated HER2/ neu, HER3, phospho-extracellular-regulated kinase-1/2 (ERK-1/2), and phospho-glycogen synthetase kinase 3alpha (GSK3alpha) and beta proteins were increased in MCF-7TAMLT tumors treated with fulvestrant compared to estradiol, control, or tamoxifen. Phospho-HER2/neu interacted with HER3 protein in MCF-7TAMLT tumors. In order to determine whether the functional interaction of HER2/neu with HER3 is critical for growth of fulvestrant-stimulated MCF-7TAMLT tumors, pertuzumab (an antibody that blocks HER2/neu-HER3 interaction) was used in an in vivo xenograft growth assay. Only growth of fulvestrant-treated MCF-7TAMLT xenografts was decreased significantly by 37.2% in response to pertuzumab (P=0.004). Pertuzumab specifically decreased the interaction of HER2/neu protein with HER3 in fulvestrant-stimulated MCF-7TAMLT tumors. These results suggested growth of MCF-7TAMLT tumors by tamoxifen or fulvestrant is potentially independent of ERalpha transcriptional activity as evidenced by lack of induction of four estrogen-responsive genes. The results suggested that growth of MCF-7TAMLT tumors treated with fulvestrant in the presence of physiologic estradiol is in part mediated through enhanced signaling from the HER2/neu-HER3 pathway as pertuzumab partially inhibited growth and the interaction of HER2/neu with HER3 in vivo.
PMID: 17203234 [PubMed - indexed for MEDLINE]
J Natl Cancer Inst. 2004 Jun 16;96(12):926-35. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer.
BACKGROUND: Patients receiving adjuvant tamoxifen whose tumors express high levels of both HER2/neu (HER2) and the estrogen receptor (ER) coactivator AIB1 often develop tamoxifen resistance. We used a breast cancer model system with high expression of AIB1 and HER2 to investigate the possible mechanisms underlying this resistance. METHODS: MCF-7 breast cancer cells, which express high levels of AIB1, and a tamoxifen-resistant derivative cell line engineered to overexpress HER2 (MCF-7/HER2-18) were treated with estrogen, tamoxifen, epidermal growth factor (EGF), or heregulin in the absence or presence of the EGF receptor (EGFR) tyrosine kinase inhibitor gefitinib. We analyzed phosphorylation of signaling intermediates by immunoblotting, ER transcriptional activity with reporter gene constructs and immunoblot analysis of endogenous gene products, promoter assembly by chromatin immunoprecipitation (ChIP) assay, and tumor cell growth in vitro by anchorage-independent colony formation and in vivo using xenografts in nude mice. RESULTS: MCF-7/HER2-18 tumors were completely growth inhibited by estrogen deprivation but were growth stimulated by tamoxifen. Molecular cross-talk between the ER and HER2 pathways was increased in the MCF-7/HER-2 cells compared with MCF-7 cells, with cross-phosphorylation and activation of both the ER and the EGFR/HER2 receptors, the signaling molecules AKT and ERK 1,2 mitogen-activated protein kinase (MAPK), and AIB1 itself with both estrogen and tamoxifen treatment. Tamoxifen recruited coactivator complexes (ER, AIB1, CBP, p300) to the ER-regulated pS2 gene promoter in MCF-7/HER2-18 cells and corepressor complexes (NCoR, histone deacetylase 3) in MCF-7 cells. Gefitinib pretreatment blocked receptor cross-talk, reestablished corepressor complexes with tamoxifen-bound ER on target gene promoters, eliminated tamoxifen's agonist effects, and restored its antitumor activity both in vitro and in vivo in MCF-7/HER2-18 cells. CONCLUSIONS: Tamoxifen behaves as an estrogen agonist in breast cancer cells that express high levels of AIB1 and HER2, resulting in de novo resistance. Gefitinib's ability to eliminate this cross-talk and to restore tamoxifen's antitumor effects should be tested in the clinic.
PMID: 15199112 [PubMed - indexed for MEDLINE]
Breast Cancer Res Treat. 2005 Aug;92(3):251-63. In vitro and in vivo effects of combination of Trastuzumab (Herceptin) and Tamoxifen in breast cancer.
Wang CX, Koay DC, Edwards A, Lu Z, Mor G, Ocal IT, Digiovanna MP.
Department of Internal Medicine (Section of Medical Oncology), Yale University School of Medicine, 333 Cedar Street, Room NSB288, 06510, New Haven, CT 06510, USA.
Extensive interactions between estrogen receptor alpha (ERalpha) and HER2 signaling pathways have been described. Using BT-474 human breast cancer cells, we have previously shown that the combination of tamoxifen (TAM) and Herceptin results in strong synergistic growth inhibition, enhancement of G(0)-G(1) cell cycle accumulation, inhibition of HER2 activity and a cytostatic effect without cell death. To further examine the underlying mechanism of synergy, we investigated the effect of this drug combination on ERalpha function and growth factor downstream signaling. TAM caused a small increase in ERalpha levels while Herceptin had no effect, and both drugs caused an increase in the level of Ser118-phosphorylated ERalpha. However, both TAM and Herceptin individually inhibited ERalpha transcriptional activity, although the combination did not have a greater effect than either single agent. Herceptin inhibited MAPK and Akt activity, while TAM had no effect on these either as a single agent or when added to Herceptin. Using a BALB/c athymic BT-474 in vivo xenograft model, the drug combination (Herceptin 0.3 mg/kg i.p. twice weekly, TAM 1.0 mg/mouse i.p. three times per week) showed a greater inhibition of tumor growth compared to either single agent. Tumor extracts and fixed sections were examined at the end of the treatment period for treatment-specific alterations: we noted a paradoxical proliferation-inducing effect of TAM that was reversed by the addition of Herceptin. Our results indicate that combined targeting of both peptide growth factor receptors and ERalpha represents a promising breast cancer treatment strategy.
J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):249-56. Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy.
Osipo C, Gajdos C, Cheng D, Jordan VC.
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Currently, the standard of care for estrogen receptor (ER)-positive breast cancer is 5 years of tamoxifen (TAM) or an aromatase inhibitor (AI) such as anastrozole. New studies indicate that extending antiestrogen therapy beyond 5 years with sequential regimens will improve disease-free survival. Based on the emerging concept that longer therapies are better, we have developed sequential models of tamoxifen-resistant breast cancer in vivo to mimic the clinical scenario of long-term antiestrogen therapy. The goal of the current study was to investigate the consequences of long-term treatment with tamoxifen on the growth of breast tumors in athymic mice. The results demonstrate that there are distinct phases of resistance to tamoxifen that correlate with time of treatment and expression of HER2/neu mRNA. In the treatment phase, 17beta-estradiol (E2) stimulated growth, while TAM inhibited growth of MCF-7 tumors (MCF-7E2). The withdrawal of treatment, mimicking the use of an AI, completely prevented growth. In Phase I resistance, the tumors (MCF-7TAMST) were growth-stimulated by either E2 or TAM, but inhibited by no treatment, fulvestrant, or E2 + fulvestrant. Phase II-resistant tumors (MCF-7TAMLT) were treated for more than 5 years and growth-stimulated by TAM. However, no treatment, fulvestrant, or E2 completely inhibited growth. Interestingly, the few tumors (MCF-7TAMLT) that survived in response to E2 were robustly re-stimulated by E2 after transplantation into new generations of athymic mice. These E2-stimulated tumors (MCF-7TAME) were inhibited by TAM in a dose-dependent similar to their parental tumors (MCF-7E2). In addition, the MCF-7TAME tumors were inhibited by either no treatment or fulvestrant. HER2/neu and HER3 mRNAs were over-expressed in TAM-stimulated MCF-7TAMLT tumors and remained high in E2-stimulated MCF-7TAME tumors. The data indicate that complete reversal of resistance to TAM can be achieved with the use of low dose E2 therapy. Also, these data suggest that over-expression of HER2/neu alone is insufficient to predict resistance to TAM. Based on the results, we suggest using an alternating treatment regimen, cycling antiestrogen with estrogen therapy to avoid drug-resistance.
PMID: 15860267 [PubMed - indexed for MEDLINE]
Clin Cancer Res. 2007 Aug 15;13(16):4882-90. Hydroxamic acid analogue histone deacetylase inhibitors (inc Vorinostat) attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90.
Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K.
Medical College of Georgia Cancer Center, Augusta, Georgia 30912, USA.
PURPOSE: The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-alpha in an active conformation, allowing it to bind 17beta-estradiol (E2) and transactivate genes, including progesterone receptor (PR)-beta and the class IIB histone deacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates alpha-tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ERalpha, as well as on the survival of ERalpha-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells. EXPERIMENTAL DESIGN: Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ERalpha, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells. RESULTS: Treatment with HA-HDI induced hsp90 hyperacetylation, decreased its binding to ERalpha, and increased polyubiquitylation and depletion of ERalpha levels. HA-HDI treatment abrogated E2-induced estrogen response element-luciferase expression and attenuated PRbeta and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal-regulated kinase-1/2 levels, inhibited growth, and sensitized ERalpha-positive breast cancer cells to tamoxifen. CONCLUSIONS: These findings show that treatment with HA-HDI abrogates ERalpha levels and activity and could sensitize ERalpha-positive breast cancers to E2 depletion or ERalpha antagonists.
Valproic acid restores ERalpha and antiestrogen sensitivity to ERalpha-negative breast cancer cells.
Fortunati N, Bertino S, Costantino L, De Bortoli M, Compagnone A, Bandino A, Catalano MG, Boccuzzi G.
Oncological Endocrinology, AUO San Giovanni Battista, Torino, Italy. Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor alpha (ERalpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ERalpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ERalpha mRNA and protein, while did not modify ERbeta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen-responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER-related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ERalpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy.
PMID: 19772891 [PubMed - as supplied by publisher
Cancer Prev Res (Phila Pa). 2010 Feb 23. [Epub ahead of print] The Impact of Fish Oil on the Chemopreventive Efficacy of Tamoxifen against Development of N-Methyl-N-Nitrosourea-Induced Rat Mammary Carcinogenesis.
Manni A, Xu H, Washington S, Aliaga C, Cooper T, Richie JP Jr, Bruggeman R, Prokopczyk B, Calcagnotto A, Trushin N, Mauger D, Verderame MF, El-Bayoumy K.
Authors' Affiliations: Departments of 1Medicine, 2Biochemistry and Molecular Biology, 3Comparative Medicine, 4Public Health Sciences, 5Pathology, and 6Pharmacology, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania.
The antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor-gamma (PPARgamma), generally exert tumor-suppressive effects. Based on the known crosstalk between the estrogen and the PPARgamma receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea-induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPARgamma is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA-rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies. Cancer Prev Res; 3(3); 322-30.
PMID: 20179301 [PubMed - as supplied by publisher]
"A common theme of many investigations into CSCs is that they have inherent resistance to chemo and radiotherapy. This is proposed to be due to mechanisms such as more efficient DNA damage checkpoints and survival pathways compared to more differentiated tumor
cell populations."
"Enhanced interaction between estrogen receptor signalling and growth factor tyrosine kinase pathways such as EGFR, HER2/erbB2 and IGFR mediates resistance to endocrine therapy"
"HDAC inhibitors are being used in a number of on going clinical trials including a phase II trial evaluating vorinostat in ER positive patients with metastatic breast cancer who failed prior aromatase inhibitor therapy and up to three chemotherapy regimes [95]. A report of preliminary findings presented at ASCO 2008 (http://tinyurl.com/ASCO-Vorino-Tam) showed that out of the 17 enrolled patients 21% had a partial response and 29% had stable disease after treatment with vorinostat 400 mg daily for 3 of 4 weeks and tamoxifen 20 mg daily, continuously. These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have failed prior aromatase inhibitors or adjuvant tamoxifen may restore hormone sensitivity."
Final results: Results: To date, 19 patients [median age 56 years (36-71)] have been enrolled and 17 patients were evaluated for response. Two patients (2/18, 11%) had a pulmonary embolus./DVT. Three patients (3/18, 17%) had Grade 3 fatigue, and one patient each (1/18, 6%) had diarrhea, nausea/vomiting, weight loss, AST/ALT elevations, neutropenia or thrombocytopenia. Predominant Grade 2 toxicities included fatigue, nausea/vomiting, anorexia, bleeding and myelosuppression. Four patients had an objective response (1 complete, 3 partial responses: 4/17, 24%), of those 50% had prior chemotherapy and 75% had failed two aromatase inhibitors for metastatic disease, 50% had failed prior tamoxifen. One additional patient had stable disease for 12 months. Ongoing phase II (same dosage) at Moffitt: http://www.clinicaltrial.gov/ct2/show/NCT00365599
"Patients with evidence of visceral crisis are not eligible for this study"
Biological Determinants of Endocrine Resistance in Breast Cancer
(Many sections at link) http://www.medscape.com/viewarticle/708394
Elizabeth A. Musgrove; Robert L. Sutherland
Published: 09/24/2009
Abstract
Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance.
Preferential killing of breast tumor initiating cells by N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine/tesmilifene.
Deng T, Liu JC, Pritchard KI, Eisen A, Zacksenhaus E.
Toronto General Research Institute-University Health Network, Ontario, Canada.
PURPOSE: N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is thought to potentiate the antineoplastic effect of cytotoxic drugs. In a phase III randomized trial for metastatic breast cancer using doxorubicin with or without DPPE, addition of the latter resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response. Here we tested the hypothesis that DPPE targets breast tumor-initiating cells (TICs). EXPERIMENTAL DESIGN: Human breast TICs from pleural effusions were identified as CD44(+):CD24(-/low) cells by flow cytometry and functionally by their ability to form nonadherent spheres in culture. Mouse mammary TICs from two different models of breast cancer were identified as cells capable of initiating spheres in culture and secondary tumors following transplantation into the mammary gland of syngeneic mice. RESULTS: We show that at physiologically attainable concentrations, treatment with DPPE alone reduced tumorsphere formation and viability of CD44(+):CD24(-/low) breast cancer cells. The kinetics of killing varied for the different breast tumor cells and required continuous exposure to the drug. Whereas doxorubicin killed CD44(+):CD24(-/low) and CD44(-):CD24(+) cells equally well, DPPE induced apoptosis preferentially in CD44(+):CD24(-/low) cells. Treatment of Her2/Neu(+) mammary tumor cells with DPPE in vitro efficiently killed TICs, as determined by flow cytometry and transplantation assays; DPPE further cooperated with doxorubicin to completely eradicate tumorigenic cells. CONCLUSIONS: Our results show that continuous treatment with DPPE alone directly targets breast TICs, and provide rationale to test for cooperation between DPPE and known drugs with efficacy toward breast cancer subtypes.
PMID: 19118039 [PubMed - indexed for MEDLINE
Tesmilifene is a Tamoxifen derivative. Please note the significant finding that is so different from the early detectable tumor shrinkage=efficacy paradigm:
"resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response."
1: Cancer Lett. 2009 Feb 18;274(2):279-89. Epub 2008 Nov 4. Links
Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene.
Ferguson PJ, Brisson AR, Koropatnick J, Vincent MD.
Lawson Health Research Institute, London Health Sciences Centre, 790 Commissioners Road, London, Ontario, Canada. peter.ferguson@uwo.ca N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine (tesmilifene), a tamoxifen derivative with antihistamine activity, greatly enhanced the survival of doxorubicin-treated, advanced stage breast cancer patients in a phase III trial. However, the molecular basis of tesmilifene action is not firmly established. The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma (HNSCC) and breast carcinoma cell lines as a model system. Multidrug resistant (MDR) variants of an HNSCC cell line, HN-5a/V15e, and a breast carcinoma cell line, MCF-7/V25a, both highly overexpressed mdr1 (ABCB1) mRNA and the proteins P-glycoprotein and glutathione transferase-pi. Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect. Tesmilifene had minimal effect on drug cytotoxicity against the parental cell lines. However, the same tesmilifene treatment enhanced cytotoxicity of docetaxel, paclitaxel, epirubicin, doxorubicin, and vinorelbine against both MDR cell lines by up to 50%. Flow cytometric measurement of annexin V/propidium iodide staining demonstrated that tesmilifene increased the killing of HN-5a/V15e cells caused by docetaxel after 24 and 48h exposure. Tesmilifene increased accumulation of radiolabelled vincristine in HN-5a/V15e cells, over 4h, by up to 100%. The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs. The mechanism of enhancement appears to be related to expression of an ABC pump-dependent, MDR phenotype.
N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene), a chemopotentiating agent with hormetic effects on DNA synthesis in vitro, may improve survival in patients with metastatic breast cancer.
Brandes LJ.
Department of Medicine and Pharmacology/Therapeutics, University of Manitoba and Section of Hematology/Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg MB R3E0V9, Canada. brandes@cc.umanitoba.ca
N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene) is a novel anti-histaminic and chemopotentiating agent that has a hormetic effect on DNA synthesis in MCF (Michigan Cancer Foundation)-7 human breast cancer cells in vitro and stimulates the growth of experimental tumors in rodents. In a prospectively randomized phase three trial (NCIC MA.19), 152 patients who were co-administered DPPE and doxorubicin survived 50% longer (P < 0.03) than 153 patients who were administered the same dose and schedule of doxorubicin alone. At clinically relevant in vitro concentrations that do not inhibit the P-glycoprotein (P-gp) pump, DPPE selectively sensitizes the cancer cells that express the multiple drug resistance phenotype, making them more susceptible to the cytotoxic effects of chemotherapeutic agents, including anthracyclines and taxanes. Based on its previously demonstrated interaction with histamine at CYP3A4, a P450 that metabolizes arachidonic acid, and its induction of high levels of prostacyclin in the gut of rodents, modulation by DPPE of the intracellular concentration of arachidonate products, such as hydroxyeicosatetraeinoic acids, implicated in increased cancer cell proliferation and metastasis, is postulated.
PMID: 18480139 [PubMed - indexed for MEDLINE
Tesmilifene has an intriguing mechanism of action and has been shown in Phase II clinical trials and in one Phase III clinical trial to enhance the activity of anthracyclines and taxanes, as well as cisplatin and 5-FU in a variety of pre-clinical models.
In clinical studies there is evidence that tesmilifene increases the cytotoxic effects of mitoxantrone and cyclophosphamide in prostate cancer and doxorubicin and taxol in metastatic breast cancer. In a Phase III study of patients with metastatic breast cancer, the addition of tesmilifene to doxorubicin resulted in a 50% increase in survival compared with doxorubicin alone. A second Phase III study of metastatic breast cancer in 723 patients treated with epirubicin/cyclophosphamide +/- tesmilifene failed to demonstrate efficacy with this chemotherapy regimen.
Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells.
Li Z, Carrier L, Rowan BG.
Department of Structural and Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Tamoxifen has efficacy as a breast cancer therapy and chemoprevention agent. However, toxicity and resistance to tamoxifen limit its clinical application. There is an urgent need to develop compounds that may be combined with tamoxifen to improve efficacy and overcome toxicity and resistance. We showed previously that the organoselenium compound methylseleninic acid (MSA) increased the growth-inhibitory effect of tamoxifen and reversed tamoxifen resistance in breast cancer cells. In this study, we examined the mechanism for induction of apoptosis by MSA combined with tamoxifen in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. 4-hydroxytamoxifen (TAM; 10(-7) mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 micromol/L) induced apoptosis in tamoxifen-sensitive cells. Combination of MSA with TAM resulted in a synergistic apoptosis in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells compared with either agent alone. MSA and MSA combined with TAM induced apoptosis through the intrinsic, mitochondrial apoptotic pathway. MSA induced a sequential activation of caspase-9 and then caspase-8. These results indicate that the growth inhibition synergy and reversal of tamoxifen resistance by combination of selenium with tamoxifen occurs via a tamoxifen-induced cell cycle arrest, allowing more cells to enter the intrinsic apoptotic pathway elicited by selenium.
PMID: 18790785 [PubMed - indexed for MEDLINE
http://mct.aacrjournals.org/content/4/8/1239.full 2005
Selenium disrupts estrogen receptor α signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells
Requests for reprints: Brian G. Rowan, Department of Structural and Cellular Biology, SL49, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112. Phone 504-988-1365; Fax: 504-988-1687. E-mail: browan@tulane.edu
Abstract
Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 μmol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10−7 mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Δ16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ERα mRNA and protein without an effect on ERβ levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE2e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ERα levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.
Carcinogenesis. 2006 Dec;27(12):2424-33. Epub 2006 Jun 19. The combination of green tea and tamoxifen is effective against breast cancer.
Sartippour MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, Sartippour G, Zhang L, Lu M, Weinberg O, Rao JY, Brooks MN.
Department of Surgery, Center for Human Nutrition, University of California, Los Angeles, CA 90095-1782, USA.
Epidemiologic data have suggested that green tea may prevent breast cancer. Studies in our laboratory have provided evidence that green tea extract inhibits breast cancer growth by a direct anti-proliferative effect on the tumor cells, as well as by indirect suppressive effects on the tumor-associated endothelial cells. In this study, we asked whether concurrent administration of green tea may add to the anti-tumor effects of standard breast cancer therapy. We observed that green tea increased the inhibitory effect of tamoxifen on the proliferation of the ER (estrogen receptor)-positive MCF-7, ZR75, T47D human breast cancer cells in vitro. This combination regimen was also more potent than either agent alone at increasing cell apoptosis. In animal experiments, mice treated with both green tea and tamoxifen had the smallest MCF-7 xenograft tumor size, and the highest levels of apoptosis in tumor tissue, as compared with either agent administered alone. Moreover, the suppression of angiogenesis in vivo correlated with larger areas of necrosis and lower tumor blood vessel density in treated xenografts. Green tea decreased levels of ER-alpha in tumors both in vitro and in vivo. We also observed that green tea blocked ER-dependent transcription, as well as estradiol-induced phosphorylation and nuclear localization of mitogen-activated protein kinase. To our knowledge, this study is the first to show the interaction of green tea with the ER pathway, as well as provide mechanistic evidence that the combination of green tea and tamoxifen is more potent than either agent alone in suppressing breast cancer growth. These results may lead to future improvements in breast cancer treatment and prevention.
PMID: 16785249 [PubMed - indexed for MEDLINE]
Br J Cancer. 2008 Oct 7;99(7):1056-63. Epub 2008 Sep 16. A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate.
Scandlyn MJ, Stuart EC, Somers-Edgar TJ, Menzies AR, Rosengren RJ.
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
We have previously shown that tamoxifen+epigallocatechin gallate (EGCG) is synergistically cytotoxic towards oestrogen receptor (ER)-negative breast cancer cells. To determine if this response would correlate with significant tumour suppression in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with tamoxifen, EGCG, EGCG+tamoxifen, or vehicle control for 10 weeks. Tumour volume in EGCG- (25 mg kg(-1))+tamoxifen (75 microg kg(-1))-treated mice decreased by 71% as compared with vehicle control (P<0.05), whereas tumour weight was decreased by 80% compared with control (P<0.01). Epigallocatechin gallate treatment did not alter ER protein expression in MDA-MB-231 cells and thus was not a mechanism for the observed tumour suppression. However, western blotting of tumour extracts demonstrated that epidermal growth factor receptor (EGFR; 85% lower than control), pEGFR (78% lower than control), mammalian target of rapamycin (mTOR; 78% lower than control), and CYP1B1 (75% lower than control) were significantly lower after the combination treatment as compared with all other treatments. Nuclear factor-kappaB (NF-kappaB), b-Raf, p-MEK, S6K, 4EBP1, Akt, vascular EGFR-1 (VEGFR-1) and VEGF expressions were decreased in control but not in the individual treatments, whereas MEK, phospholipase D 1/2, TGF alpha, and ERK expressions were not changed after any treatment. The results demonstrate that tamoxifen at realistic doses (75 mug kg(-1)) can suppress the growth of ER-negative breast cancer when combined with EGCG. In addition, the dominant mechanism for tumour suppression is the concomitant decrease in tumour protein expressions of mTOR and the EGFR.
Cancer Chemother Pharmacol. 2009 May 20. [Epub ahead of print] Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer.
Kurebayashi J, Nukatsuka M, Sonoo H, Uchida J, Kiniwa M.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan, kure@med.kawasaki-m.ac.jp.
PURPOSE: Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study. METHODS: Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated. RESULTS: Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study. CONCLUSIONS: These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer.
PMID: 19455332 [PubMed - as supplied by publisher]
Cancer Chemother Pharmacol. 2007 Mar;59(4):515-25. Epub 2006 Aug 10. Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells.
Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, Sugimoto Y, Oka T, Sonoo H.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. kure@med.kawasaki-m.ac.jp
PURPOSE: The sequential addition of tamoxifen (TAM) to chemotherapy seems superior to its concurrent addition in patients with breast cancer. This study was conducted to clarify the hypothesis that there are differential interactions among TAM and chemotherapeutic agents. METHODS: Estrogen receptor (ER)-alpha-positive or -negative breast cancer cells were treated with 4-hydroxy TAM (4OHT), 5-fluorouracil (FU) and/or doxorubicin (Dox). Changes in the expression levels of genes related to sensitivity and resistance to TAM, 5-FU or Dox were tested. RESULTS: Concurrent treatment of 4OHT with 5-FU but not with Dox additively inhibited the growth of ER-alpha-positive cells. 5-FU did not change the expression levels of any tested genes related to either sensitivity or resistance to TAM. Although Dox did not change the expression levels of any genes related to the sensitivity to TAM, Dox significantly increased the expression levels of some genes related to TAM resistance, Eph A-2, ER-beta, Fos and vascular endothelial growth factor. 4OHT significantly decreased thymidilate synthase (TS) activity. CONCLUSIONS: Although the antitumor effect of concurrent 4OHT and 5-FU was additive, that of concurrent 4OHT and Dox was less than additive in ER-alpha-positive cells. The increased expression of genes related to TAM resistance by Dox might be responsible for the interaction. Decreased TS activity by 4OHT might increase the antitumor activity of 5-FU. These findings may provide a preclinical rationale for concurrent use with 5-FU and TAM.
PMID: 16900372 [PubMed - indexed for MEDLINE]
In vivo and in vitro efficacy of capecitabine (X) + tamoxifen (TAM) in breast cancer (BC)
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 21092
K. Mori, Y. Yamaguchi, N. Sawada, K. Kondoh and S. Hayashi Chugai Pharmaceutical Co, Kamakura, Japan; Saitama Cancer Center, Ina-machi, Japan; School of Medicine, Tohoku University, Sendai, Japan 21092 Background:In vitro studies in BC cell lines suggested antagonismbetween TAM and 5-FU. Thymidine phosphorylase (TP) activatesX to 5-FU in tumors. X activity correlates with tumor TP concentrationsin vivo. Methods: We studied antitumor efficacy of X + TAM invivo and in vitro in human BC models. Nude mice were inoculateds.c. with estradiol, then MCF-7 cells 1 day later. When tumorswere 300 mm3, mice received 6 weeks’ oral vehicle (control),X (d1–14 q21d) at MTD (539 mg/kg) or 2/3 MTD, and/or TAMat 100 or 30 mg/kg/d. We also analyzed impact of 5-FU and doxifluridine(5'-DFUR, an intermediate of X) + TAM on estrogen receptor (ER)signals in an in-vitro culture system. ER signals were monitoredby expression of green fluorescent protein (GFP) in MCF-7 BCcells transfected with the estrogen-responsive element (ERE)-GFPgene (MCF-7-E10). GFP expression was induced in MCF-7-E10 cellsin the presence of estradiol at 3 pM or BC tissue supernatant.Results:X at 2/3 MTD + TAM 30 mg/kg were significantly moreactive than the highest dose of X or TAM alone. Tumor TP concentrationswere significantly higher in TAM- than vehicle-treated mice.In the ER signal system, GFP expression of MCF-7-E10 was reducedby 4-hydroxytamoxifen (4-OHT, active form of TAM) at 0.01 and0.1 nM. When added to 4-OHT, 5-FU 0.3–30 µM or 5'-DFUR3–10 µM reduced GFP expression more than eitheragent alone. In vitro, 5-FU and 5'-DFUR inhibited proliferationof MCF-7-E10 cells regardless of 4-OHT. Additive effects couldnot be confirmed as 4-OHT alone showed only marginal anti- proliferativeactivity at 0.01–0.1 nM. Conclusion: X and TAM are notantagonistic in this model. TAM may augment X activity via TPupregulation in BC tissues. TAM and X intermediates showed noclear antagonism in vitro in an ER signal system. All-oral X+ TAM merits evaluation as combination therapy in breast cancer.
Br J Cancer. 1997;75(6):884-91. Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis.
Ferlini C, Scambia G, Distefano M, Filippini P, Isola G, Riva A, Bombardelli E, Fattorossi A, Benedetti Panici P, Mancuso S.
Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy.
The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.
Br J Cancer. 1999 Jan;79(2):257-63. Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines.
Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C, Ferrandina G, Fattorossi A, Isola G, Benedetti Panici P, Mancuso S.
Laboratory of Antineoplastic Pharmacology, Zeneca, Rome, Italy.
Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-kappaB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 microM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 microM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein.
The present study was designed to investigate the modulatory effect of the anti-estrogen, tamoxifen (Tam) on epirubicin (Epi) cytotoxicity in breast cancer cell lines; MCF-7 and NCI-adr. Using sulphorhodamine-B assay, NCI-adr cell line was found to be five-folds more resistant to the cytotoxic effect of Epi as compared to MCF-7 cell line. Pretreatment of cells with Tam was observed to enhance Epi cytotoxicity by 4.3- and 6.5-folds in MCF-7 and NCI-adr cells, respectively. Tam-Epi interaction was found to be additive in MCF-7 cells and synergistic in NCI-adr cells. Flowcytometric DNA ploidy analysis revealed that, Epi induced cell arrest at G2/M phase. Tam pretreatment enhanced the blocking activity of low dose of Epi in MCF-7 and induced nearly two-fold increase in the percentage of S phase in NCI-adr cells. Determination of cellular Epi level revealed that Tam induced a significant increase in intracellular Epi accumulation only in NCI-adr cells after 48 h. However, analysis of P-gp function revealed that Tam failed to modulate P-gp function in both cell lines. Also, assessment of topoisomerae IIalpha gene expression showed that neither Epi nor Tam managed to change its expression level. In conclusion, Tam potentiates Epi cytotoxicity in sensitive and resistant breast cancer cell lines.enhancement of cell accumulation in S and G2/M phase, at which the cells are most sensitive to the cytotoxic effect This potentiation can be explained by an of Epi as well as an increase in the intracellular level of Epi in resistant cell line.
PMID: 16005435 [PubMed - indexed for MEDLINE
1: Cancer Lett. 1996 Nov 12;108(1):7-14. Links
Tamoxifen synergizes the antiproliferative effect of cisplatin in human ovarian cancer cells: enhancement of DNA platination as a possible mechanism.
Ercoli A, Scambia G, De Vincenzo R, Alimonti A, Petrucci F, Fattorossi A, Isola G, Benedetti Panici P, Caroli S, Mancuso S.
Department of Gynecology, Catholic University, Rome, Italy.
We investigated the chemosensitizing activity of tamoxifen (TAM) on estrogen receptor negative ovarian cancer cell lines sensitive (A2780 WT) and resistant to cisplatin (CP) (A2780 CP3). Our results showed that the treatment of both cell lines with the association TAM + CP (concentration range 0.01-1 microN and 0.1-1 microgram/ml, respectively) results in a synergistic antiproliferative activity and a complete reversal of the acquired CP-resistant phenotype. We demonstrated that in A2780 cells the addition of TAM to CP treatment is able to significantly enhance at every tested CP dose (P < 0.001) the amount of platinum (Pt) bound to the DNA. Since Pt-DNA levels in the genome are clearly related to the growth inhibitory effect of CP (correlation value = 0.97, P < 0.001) in our experimental model, we hypothesized that TAM could act synergistically with CP and overcome the acquired CP-resistance by enhancing Pt binding to the DNA. We suggest that, from a clinical point of view, TAM may be usefully included in CP-based chemotherapy regimens for ovarian cancer patients since plasma concentrations of the drug capable of in vitro CP resistance modulation are achievable in vivo. A prospective clinical trial to verify the clinical usefulness of combined TAM + CP treatment in ovarian cancer patients refractory to prior Pt-based chemotherapy is now underway in our department.
Cancer Chemother Pharmacol. 1995;36(5):368-72. Effect of tamoxifen on mitoxantrone cytotoxicity in drug-sensitive and multidrug-resistant MCF-7 cells.
Desai PB, Bhardwaj R, Damle B.
Division of Medicinal Chemistry and Pharmaceutics, School of Pharmacy, Northeast Louisiana University, Monroe 71209-0470, USA. The influence of the antiestrogen tamoxifen (TAM) on the activity of mitoxantrone (MXN), was evaluated against wild-type MCF-7/WT and their multidrug-resistant variant MCF-7/ADR cells. Multidrug resistance (MDR) in this cell line which was selected for resistance to Adriamycin (ADR), is associated with increased expression of P-glycoprotein (P-gp). In a clonogenic assay it was observed that TAM (1-10 microM) significantly enhanced the activity of MXN in the MCF-7/ADR but not in the drug-sensitive cell line. Isobologram analysis indicated that the effect of the combination was additive in the parental MCF-7/WT cells and strongly synergistic in the MDR MCF-7/ADR cells. Also, TAM (10 microM) caused a three-fold increase in the steady-state levels (Css) of MXN in MCF-7/ADR cells but did not modulate MXN levels in MCF-7/WT cells. The observed synergism in MCF-7/ADR cells was perhaps due to the increase in Css of MXN that may involve interaction of TAM with P-gp. The combination of MXN and TAM may be useful in the treatment of drug-sensitive and drug-resistant breast cancer.
PMID: 7634377 [PubMed - indexed for MEDLINE]
Anticancer Drugs. 2007 Sep;18(8):923-31. Enhancement of the antitumor activity of tamoxifen and anastrozole by the farnesyltransferase inhibitor lonafarnib (SCH66336, Sarasar).
Liu G, Marrinan CH, Taylor SA, Black S, Basso AD, Kirschmeier P, Robert Bishop W, Liu M, Long BJ.
Department of Biological Research - Oncology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. Lonafarnib is an orally bioavailable farnesyltransferase inhibitor. Originally developed to block the membrane localization of Ras, subsequent work suggested that farnesyltransferase inhibitors mediate their antitumor activities by altering the biological activities of additional farnesylated proteins. Breast tumor models that express wild-type Ras have been shown to be sensitive to farnesyltransferase inhibitors. We have determined the effects of combining lonafarnib with the antiestrogen 4-hydroxy tamoxifen on hormone-dependent breast cancer cell lines in vitro. The effects of combining lonafarnib with tamoxifen or the aromatase inhibitor anastrozole on the growth of two different MCF-7 breast tumor xenograft models were also evaluated. In four of five human breast cancer cell lines, lonafarnib enhanced the antiproliferative effects of 4-hydroxy tamoxifen. The combination prevented MCF-7 cells from transitioning through the G1 to S phase of the cell cycle and augmented apoptosis. This was associated with reduced expression of E2F-1 and a reduction in hyperphosphorylated retinoblastoma protein. Lonafarnib plus 4-hydroxy tamoxifen also inhibited the mammalian target of rapamycin signal transduction pathway. In nude mice bearing parental MCF-7 or aromatase-transfected MCF-7Ca breast tumor xenografts, lonafarnib enhanced the antitumor activity of both tamoxifen and anastrozole. These studies indicate that lonafarnib enhances the efficacy of endocrine agents clinically used for treating hormone-dependent breast cancer.
Chemo Followed by Tamoxifen Augments Survival in ER+ Breast Cancer
As Reported by HealthDay News. 2009 Dec 11
Postmenopausal women who have estrogen-receptor (ER)−positive breast cancer may be able to improve their survival if they receive treatment with a combination of chemotherapy and tamoxifen. Traditionally, such patients are given tamoxifen, which blocks estrogen receptors. However, researchers have speculated that women with ER-positive breast cancer might benefit from also receiving chemotherapy.
Researchers at Loyola University Chicago Stritch School of Medicine compared the survival benefits of 4 different regimens in 1460 patients, whom they followed for up to 13 years (median, 9 years). The regimens compared were tamoxifen alone, chemotherapy alone, tamoxifen plus chemotherapy given simultaneously, and chemotherapy followed by tamoxifen. All of the patients had positive lymph nodes. Tamoxifen was taken for 5 years. The chemotherapy regimen consisted of cyclophosphamide, doxorubicine (Adriamycin), and 5-fluorouracil.
Compared with tamoxifen alone, the combination of chemotherapy with tamoxifen increased disease-free survival by 24%. Sequential administration of chemotherapy followed by tamoxifen was slightly more beneficial than simultaneous tamoxifen plus chemotherapy. Estimated disease-free survival at 10 years was 48% for the tamoxifen-alone group, as compared with 57% for the group receiving both chemotherapy and tamoxifen.
The research results were published in the December 10 online issue of The Lancet and were presented on December 10 at the San Antonio Breast Cancer Symposium.
Health News Adding Chemo to Tamoxifen Helps Some Breast Cancer Patients
12/11/2009
THURSDAY, Dec. 10 (HealthDay News) -- Adding chemotherapy to standard cancer-suppressing tamoxifen can boost survival in postmenopausal women with the most common type of breast cancer, known as estrogen receptor-positive, and it's best given before the tamoxifen regimen starts, according to a new study.
"Chemotherapy with Adriamycin adds to your survival benefit over and above what tamoxifen would do if you are postmenopausal and have positive lymph nodes and estrogen receptor-positive cancer [the most common type]," explained Dr. Kathy Albain, the lead researcher and professor of medicine at Loyola University Chicago Stritch School of Medicine.
And in another study, Albain found that screening breast tumors with an available multi-gene test spots patients who may not need this form of chemotherapy, despite fitting the standard profile.
Both studies are published online Dec. 10, the first in the journal The Lancet and the second in The Lancet Oncology. Albain is also due to present her findings Thursday at the annual San Antonio Breast Cancer Symposium in San Antonio, Texas.
In estrogen receptor-positive cancer, tumor cells carry many receptors on their surfaces to which estrogen can attach, fueling tumor growth. Tamoxifen works by blocking the receptors.
Experts have long debated whether women with estrogen receptor-positive cancers -- whose growth is fueled by circulating estrogen -- would get more benefit from having a chemotherapy regimen on top of tamoxifen.
Albain led a research team from multiple centers that followed nearly 1,500 breast cancer patients for up to 13 years, with a median (half longer, half less) of nearly nine years. All were past menopause and had hormone receptor-positive cancer that had spread to at least one lymph node in the armpit area.
Albain's team assigned 381 women to tamoxifen alone, 587 to chemotherapy alone and 590 to both, with some receiving tamoxifen and chemo together and some in a sequential manner.
Tamoxifen was taken daily for five years. The chemo regimen used is called CAF, for "cyclophosphamide, Adriamycin and 5-fluorouracil."
In all, after accounting for study dropouts, 1,460 women received treatment.
The combined treatments of chemo plus tamoxifen increased the women's disease-free survival by 24 percent, Albain found. When her team looked at which delivery protocol worked best -- simultaneous tamoxifen and chemotherapy or chemo followed by tamoxifen -- the sequential approach was found to be better, giving slightly better disease-free survival.
Ten-year disease-free survival estimates were 57 percent for the combination group and 48 percent for the tamoxifen-only group, the researchers found.
However, women receiving chemo were more likely to have drops in white blood cells, important for fighting infections, the team noted. And they were also more prone to blood clots, congestive heart failure and other complications.
In a second study, Albain's team analyzed whether a gene test, called Oncotype DX, could predict which women would benefit from chemotherapy. Genomic Health, which makes the test, helped fund the study, along with the U.S. National Cancer Institute.
The test, which Albain said is already widely used, is done on the tumor itself. "This puts 21 genes together and comes up with a score," she said. The score -- low, intermediate, high -- predicts the risk of recurrence over 10 years if a woman used tamoxifen alone.
When the researchers performed the test on 367 specimens, they found a low score identified those women who may not need the chemo, despite the fact that they have cancer that spread to lymph nodes.
"This is a positive study, there's no question," said Dr. Joanne Mortimer, vice chair of medical oncology for the City of Hope Cancer Center in Duarte, Calif., of the first study. "This study tells us [that] if you have positive lymph nodes [and are postmenopausal with estrogen receptor-positive cancer], you should have both chemo and tamoxifen, because the survival was better."
But, she added, "when you give everyone [who has the estrogen receptor-positive, node-positive breast cancer] chemotherapy, probably there are some who don't need it."
According to Mortimer, that's why the gene test looks promising -- it may spare some women from having to have chemo while ensuring that those who will benefit from the treatment get it.
With the cost of new cancer drugs soaring to $10,000 a month or more, genomic analyses of cancer tumors hold out the hope that oncologists will be able to identify in advance which patients will benefit from use of pricey new drugs. A new draft report from the Agency for Healthcare Research and Quality suggests that day is still a ways off. In the finding most likely to cause controversy, the AHRQ report found there was "no consistent associations" between breast cancer patients with the relevant CYP2D6 polymorphism and the outcome of tamoxifen therapy, whether as primary treatment or in as post-operative adjuvant therapy. Estimates vary, but anywhere from 10 to 40 percent of women have the gene variant of CYP2D6 that is believed to slow the metabolism of tamoxifen and make it less effective. A number of companies sell a $300 test that can show if women have the allegedly telltale CYP2D6 polymorphism.
As is often the case, the 13 studies identified by the systematic review didn't contain enough data to draw definitive conclusions. "Most studies were relatively small and thus underpowered to detect what would be a plausible effect size for the modification of response to tamoxifen by a single polymorphism," the report noted.
Discovery could aid cancer care
(UKPA) – 6 hours ago
A new gene discovery could lead to more personalised treatment for breast cancer patients, scientists announced.
Experts have identified a gene, FKBPL, which predicts how women will respond to the commonly used drug tamoxifen.
The medicine interferes with the activity of the female hormone oestrogen, and is suitable for women with hormone sensitive breast cancer.
About 28,000 women in the UK are diagnosed with this type of cancer each year and thousands are given tamoxifen for five years after an initial round of treatment or surgery.
However, not all women respond to the drug and it is estimated that only around two-thirds actually benefit.
Now, scientists at Queen's University Belfast have found that high levels of FKBPL in breast cancer cells suggest a woman will respond well to tamoxifen and have a better chance of survival than women with low levels of the gene.
Tracy Robson and Hayley McKeen published the study, funded by the charity Breast Cancer Campaign, in the journal Cancer Research.
Dr Robson said: "I believe that many women are being treated with tamoxifen without knowing whether it will benefit them.
"This research is a step in the right direction towards personalised treatment, ensuring that appropriate therapies are given right at the point of diagnosis, avoiding unnecessary treatment.
"More importantly this research should allow us to identify which patients are unlikely to respond to or eventually relapse on tamoxifen therapy, which means they could be treated more aggressively with chemotherapy."
Same month:
J Clin Oncol. 2010 Feb 1. [Epub ahead of print] Significant Effect of Polymorphisms in CYP2D6 and ABCC2 on Clinical Outcomes of Adjuvant Tamoxifen Therapy for Breast Cancer Patients.
Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M, Tanigawara Y, Flockhart DA, Desta Z, Skaar TC, Aki F, Hirata K, Takatsuka Y, Okazaki M, Ohsumi S, Yamakawa T, Sasa M, Nakamura Y, Zembutsu H.
Laboratories for Pharmacogenetics, Genotyping Development, and Medical Informatics, RIKEN Center for Genomic Medicine, Yokohama; Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo; Department of Surgery, Itoh Surgery and Breast Clinic; Department of Surgery, Yamakawa Breast Clinic, Kochi; First Department of Surgery, Sapporo Medical University; Department of Surgery, Sapporo Breast Surgical Clinic, Sapporo; Department of Breast Surgery, Kansai Rosai Hospotal, Hyogo; Department of Breast Oncology, Shikoku Cancer Center, Ehime; Department of Surgery, Tokushima Breast Care Clinic, Tokushima, Japan; and Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
PURPOSE: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. PATIENTS AND METHODS: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. RESULTS: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with
Breast Cancer Res Treat. 2010 Jul 1. [Epub ahead of print] Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen.
Endoxifen, the most active metabolite of the prodrug tamoxifen, is produced by cytochrome P450 CYP2D6. Breast cancer patients treated with tamoxifen who have reduced CYP2D6 activity, related to either genetic variation or drug inhibition, may have inferior outcomes. To assess the effect of concomitant CYP2D6 inhibiting drug use on clinical outcomes of breast cancer patients treated with adjuvant tamoxifen. We conducted a retrospective database analysis. Women with non-metastatic estrogen receptor positive tumors who had completed adjuvant tamoxifen therapy for 2 years, without treatment with adjuvant aromatase inhibitors or early relapse, were included. Patients were classified as users of CYP2D6 inhibitors if they purchased strong CYP2D6 inhibiting drugs for >/=4 consecutive months during tamoxifen treatment. Tumors were classified as "high risk" if adjuvant chemotherapy was prescribed. Primary endpoint was disease free (DFS) and secondary endpoint was overall survival (OS). 902 patients treated with tamoxifen (median duration, 4.9 years) were followed for a median period of 5.9 years. Fifty-nine (6.5%) patients were users of CYP2D6 inhibitors (median duration, 23 months). DFS at 3 years (corresponding to 5 years after tamoxifen initiation) did not differ between users and non-users of CYP2D6 inhibiting drugs (92.7 vs. 93.0%, respectively; adjusted P = 0.44). OS at 3 years was lower in the patients using CYP2D6 inhibiting drugs: 89.4 vs. 93.8%, but after adjustment for age and comorbidities this difference was not significant (P = 0.20). Overall recurrence rates did not differ between users and non-users of CYP2D6 inhibiting drugs (11.8 vs. 19.0% respectively, P = 0.23). Concomitant prolonged therapy with strong CYP2D6 inhibiting drugs does not affect adversely DFS and recurrence rates in tamoxifen-treated early breast cancer patients.
PMID: 20593233 [PubMed - as supplied by publisher]
Ann N Y Acad Sci. 2009 Feb;1155:99-111. Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen.
Lazarus P, Blevins-Primeau AS, Zheng Y, Sun D.
Cancer Control and Population Sciences Program, Penn State Cancer Institute, Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA. plazarus@psu.edu
Tamoxifen (TAM) is a selective estrogen receptor modulator that is widely used in the prevention and treatment of estrogen receptor-positive (ER(+)) breast cancer. Its use has significantly contributed to a decline in breast cancer mortality, since breast cancer patients treated with TAM for 5 years exhibit a 30-50% reduction in both the rate of disease recurrence after 10 years of patient follow-up and occurrence of contralateral breast cancer. However, in patients treated with TAM there is substantial interindividual variability in the development of resistance to TAM therapy, and in the incidence of TAM-induced adverse events, including deep vein thrombosis, hot flashes, and the development of endometrial cancer. This article will focus on the UDP glucuronosyltransferases, a family of metabolizing enzymes that are responsible for the deactivation and clearance of TAM and TAM metabolites, and how interindividual differences in these enzymes may play a role in patient response to TAM.
PMID: 19250197 [PubMed - indexed for MEDLINE]
Scientists crack the code to tamoxifen resistance
WEDNESDAY 12 NOVEMBER 2008
Cancer Research UK Press Release CANCER RESEARCH UK scientists have discovered the molecular basis for tamoxifen response in breast cancer cells - and the reason why some women can develop resistance to the treatment, according to a study published in Nature* today (Wednesday).
Tamoxifen is given to most women for five years after they are first diagnosed with breast cancer to help prevent the disease from coming back but some women develop resistance to the treatment after time, meaning their cancer is more likely to return.
Researchers at the Cancer Research UK Cambridge Research Institute have discovered for the first time the mechanism by which the breast cancer therapy tamoxifen operates. It switches off a breast cancer gene ErbB2 via a protein called Pax2. Pax2 acts as a 'switch' to keep ErbB2 switched off. Tamoxifen resistance occurs when ErbB2 remains switched on.
Previously it was known that tamoxifen worked by blocking oestrogen from causing unchecked cell growth in breast cancer by switching certain genes on but the mechanism by which this occurred was unknown.
Lead author, Dr Jason Carroll said: "We knew that women developed resistance to tamoxifen but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked. Now we understand how all the engine parts operate and we can try to think about ways to make repairs. "We have discovered that for tamoxifen to work it has to block the gene ErbB2 and it does this by using a control switch that is hidden in the background of the genome, within the ErbB2 gene itself. In order for tamoxifen to be effective, this switch must be held in the off position by Pax2. Now we understand how women can develop tamoxifen resistance."
The production of oestrogen can cause breast cancer cells to grow and divide but tamoxifen prevents oestrogen from causing breast cancer cells to grow, helping to lower the risk of the disease returning. Most women have breast cancers that are stimulated to grow by oestrogen but not all.**
Breast cancer is the most common cancer in women in the UK. More than 45,500 women are diagnosed with the disease each year – 125 women a day, and the disease causes almost 12,500 deaths each year. Eight in 10 cases of breast cancer are diagnosed in women over the age of 50. Professor Sir David Lane, Cancer Research UK's chief scientist said: "Cancer Research UK's early clinical trials of tamoxifen helped transform the way that women were treated for early breast cancer saving ten's of thousands of lives, and this work is yet another step forward.
"More women are surviving breast cancer than ever before thanks to improvements in diagnosis and treatment as well as important fundamental science discoveries like this."
He added: "Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women.
"Understanding why it occasionally stops working is really important because it allows us to identify new targets for drug development and who will need such treatments."
ENDS
For media enquiries please contact the press office on 020 7061 8300 or, out-of-hours, the duty press officer on 07050 264 059. Notes to Editors:
Listen to Dr Carroll talking about his work:
Antoni Hurtado et al. *ERBB2 regulation by Estrogen Receptor-Pax2 determines tamoxifen response. (2008) Nature. Wednesday 12 November.
The scientists used microarray technology (genomic technology) to define a genomic map of where oestrogen receptor interacts with the genome. The oestrogen receptor was found to interact with unexpected areas in the genome, which were then identified as the 'switches' for gene regulation. This provided insight into how oestrogen receptor worked. Using this information, the scientists could find the switch for the important cancer related gene, ErbB2.
Microarray technology involves scanning millions of DNA sequences to detect the association with a target sequence of DNA (in this case the regions of the genome that make contact points with the oestrogen receptor).
New Take On Growth Factor Signaling In Tamoxifen Resistance
ScienceDaily (June 22, 2009) — Differences in growth factor (GF) signaling may cause the poor prognosis in some breast cancer cases. A new study, published in the open access journal BMC Medical Genomics, suggests that some estrogen receptor-positive breast cancers respond poorly to tamoxifen because of increased GF signaling.
Sherene Loi, from the Peter MacCallum Cancer Centre, Melbourne, worked with a team of Australian and Belgian researchers to investigate the differences between those estrogen receptor positive (ER+) cancers that respond well to tamoxifen (luminal-A) and those that do not (luminal-B). She said, “This is the first study specifically investigating the biology of the luminal-B, ER+ breast cancer subtype. We propose that activation of GF signaling contributes to this highly proliferative, relatively tamoxifen-insensitive, phenotype and that this exists independently of HER2 overexpression. Targeting this pathway and its upstream mediators could prove to be a useful therapeutic strategy”.
The researchers used a new computational method of analysis of gene expression data called gene set enrichment analysis (GSEA) to determine that there is increased growth factor activation from the gene expression profiles of nearly 100 luminal-B breast cancers samples. They then validated this finding by showing that treatment with the growth factor heregulin, which induced growth factor signaling an in-vitro model, could overcome tamoxifen-induced cell cycle arrest.
This research represents a departure from the informative, but sometimes not terribly useful, process of identifying genes associated with given conditions. Dr Loi said, “Although gene expression data has demonstrated its ability to identify subsets of disease and predict outcomes or drug responses, identifying new therapeutic approaches based on whole genome microarray profiling has, to date, been a significant challenge. By using GSEA, we’ve been able to use gene expression data to identify that activation of GF signaling pathways as a possible therapeutic target for further exploration in the clinical setting for these particular breast cancer patients”.
Imachi H et al. – Menin can function as a transcriptional regulator of ER? and is a possible predictive factor for tamoxifen resistance. Methods
Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1); it also serves as a critical link in the recruitment of nuclear receptor-mediated transcription.
Results
Menin expressed in breast cancer cell line MCF-7 is colocalized with ER? and functions as a direct coactivator of ER-mediated transcription in breast cancer cells
In MCF-7 cells, coexpression of menin and estrogen-response element-luciferase induced the activity of the latter in a hormone-dependent manner
Cells knocked down for ER? exhibited impaired ERE-luciferase activity induced by menin
Mammalian two-hybrid assay and GST pull-down assays indicated that menin could interact with the AF-2 domain of ER?
Tamoxifen inhibited the binding of menin to AF-2 in mammalian two-hybrid assay, but in menin-overexpressing clones, tamoxifen suppressed ERE-luciferase activity only to the levels of nontreated wild-type MCF-7
In a clinical study with 65 ER-positive breast cancer samples—all of which had been treated with tamoxifen for 2–5 years as adjuvant therapies—menin-positive tumors had a worse outcome than menin-negative ones
Recently, researchers have uncovered new clues how breast cancer cells become resistant to the drug tamoxifen. According to scientists at Georgetown University Medical Center in Washington, D.C., they feel that receptors on the surface of breast cancer cells may be the key.
According to the study, tamoxifen-resistant breast cancer cells display few of the alpha estrogen receptors that the drug is designed to bind with and inhibit. Instead, they display many more gamma estrogen-related receptors, which tamoxifen appears to activate.
They also tracked how, as tamoxifen resistance increases, breast cancer cells gradually lose their alpha receptors while gaining more estrogen-related gamma receptors.
The study was just published in the November 1st issue of the journal Cancer Research. It gives a clearer understanding of the importance of the gamma estrogen-related receptor in breast cancer. This receptor had not been viewed with much importance in any type of breast cancer. All that was known was that there were more of these receptors in breast cancer than in normal breast tissue.
The findings could also help to explain why invasive lobular carcinoma, the subtype studied, may not respond as well to tamoxifen as other breast cancer subtypes. The study may give scientists a good first step toward clarifying the role that tamoxifen resistance apparently plays in treatment of invasive lobular cancer.
It is why a breast cancer patient should test the tumor first by submitting the surgical specimen to an assay lab to tell if Tamoxifen would work on the receptors on the surface of breast cancer cells, or something else.
Cancer Res. 2009 Feb 15;69(4):1695. Zhu, Yuelin [added].
One-third of all estrogen receptor (ER)-positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers each year and, whereas the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of ERalpha and increased expression of the estrogen-related receptor gamma (ERRgamma). Knockdown of ERRgamma in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRgamma blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRgamma-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRgamma/AP1 signaling in the development of TAM resistance and suggest that expression of ERRgamma may be a marker of poor TAM response.
J Membr Biol. 2001 May 15;181(2):125-35. Inhibition of glial Na+ and K+ currents by tamoxifen.
Smitherman KA, Sontheimer H.
Department of Neurobiology and Cell Biology and Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Tamoxifen (tmx) is a non-steroidal triphenylethylene derivative that is predominantly known as a competitive antagonist at the estrogen receptor and is used in the treatment of breast cancer. Recent studies suggest that tamoxifen is also beneficial in the treatment of brain metastases and primary brain tumors. Tmx accumulates in brain and its concentration can be up to 46-fold higher than in serum. Therefore, astrocytes may be exposed to tmx in vivo. We use the whole-cell patch-clamp technique to examine the effects of tmx on voltage-dependent cation currents in rat cortical cultures. Using biophysical and pharmacological methods, we isolate sustained and transient outward potassium currents (I(KS) and I(KT), respectively), inwardly rectifying potassium currents (I(KIR)), and transient inward sodium currents (I(Na)). We show that that TTX-sensitive I(Na) is completely inhibited by 10 microm tmx within 5 min. Similarly, tmx blocks I(KS), but does not inhibit I(KT) or I(KIR) at these concentrations. Tmx effects are irreversible with 10 min wash. Interestingly, the currents sensitive to tmx are important in growth control of glial cellsincubation with tmx significantly reduces cell proliferation as examined by 3[H]-thymidine uptake (MacFarlane & Sontheimer, 1997). Therefore, we examine cytotoxic and proliferative effects of tmx. Tmx (10 microm) is not cytotoxic as judged by trypan blue exclusion. However, .
SOLTAMOX is a sugar-free, clear colorless liquid, with licorice and aniseed odor and taste. It is supplied in a 150mL bottle. Each 5mL dose contains 15.2 mg tamoxifen citrate, which is equivalent to 10 mg tamoxifen. The recommended daily dose is 20-40 mg. Dosages greater than 20 mg per day should be divided into morning and evening doses. A 20 mg dose of SOLTAMOX is administered as 10mL of the oral solution.
I finished Herceptin in Sept. and my onc wanted me to wait a bit before starting the hormone therapy as I felt a bit nauseated on Herceptin.
Now I hope I didn't wait too long to begin hormone therapy? Does anyone know the optimal time to start?
I am weakly ER+ so my benefit, as I have said before, is about 4-6%. I have very few symptoms on the Tamoxifen; some achy joints once in awhile that get me early in the a.m. and wake me up but no hot flashes or not many at least. How do I know it's working?
Questions, questions
Dianne
__________________
Three years and 5 months NED
Dx: Aug 2008 right breast IDC with 50% of tumor DCIS, Stage II or IIA, tumor size: 2.1 cm
Grade 3
8/9 Richardson/Bloom test
ER+ weakly positive
Alred Score: 4 (suggesting I would strongly benefit from hormone therapy)
PR-,
HER2 positive +++
No vascular invasion
No lymph nodes involved
Surgery: Sept. 9, 2008 -Modified radical mastectomy, right breast. I chose to have a simple mastectomy on the left. Began Taxotere/Carboplatin/Herceptin November, 2008. Finished T/C March 2009. Finished #16 Herceptin Sept. 09. AI's and Tamoxifen made me sick. Began natural Tamoxifen which is Quercetin, I3C and a combo of other supplements. I am also a DES Daughter. There is now a link between DES exposure in utero and breast cancer!
What is the benefit from Soltamox vs regular Tamoxifen?
Dianne
__________________
Three years and 5 months NED
Dx: Aug 2008 right breast IDC with 50% of tumor DCIS, Stage II or IIA, tumor size: 2.1 cm
Grade 3
8/9 Richardson/Bloom test
ER+ weakly positive
Alred Score: 4 (suggesting I would strongly benefit from hormone therapy)
PR-,
HER2 positive +++
No vascular invasion
No lymph nodes involved
Surgery: Sept. 9, 2008 -Modified radical mastectomy, right breast. I chose to have a simple mastectomy on the left. Began Taxotere/Carboplatin/Herceptin November, 2008. Finished T/C March 2009. Finished #16 Herceptin Sept. 09. AI's and Tamoxifen made me sick. Began natural Tamoxifen which is Quercetin, I3C and a combo of other supplements. I am also a DES Daughter. There is now a link between DES exposure in utero and breast cancer!
Soltamox is simply a liquid version. Useful if you have difficulty swallowing pills. (just added that info to the post)
You might ask about getting the Tamoxitest to gauge your metabolism of Tamoxifen. The test, according to the makers, also has value in gauging your metabolism of other medicines that travel the same pathway. Click here to download an information package on Tamoxitest
Nope, no difficulty in swallowing pills! Esp. small ones such as Tamoxifen.
I did do a DNA test that said I am a normal metabolizer for Tamoxifen as well as many other drugs. This is a good thing...too bad I'm only weakly ER positive eh?
Dianne
__________________
Three years and 5 months NED
Dx: Aug 2008 right breast IDC with 50% of tumor DCIS, Stage II or IIA, tumor size: 2.1 cm
Grade 3
8/9 Richardson/Bloom test
ER+ weakly positive
Alred Score: 4 (suggesting I would strongly benefit from hormone therapy)
PR-,
HER2 positive +++
No vascular invasion
No lymph nodes involved
Surgery: Sept. 9, 2008 -Modified radical mastectomy, right breast. I chose to have a simple mastectomy on the left. Began Taxotere/Carboplatin/Herceptin November, 2008. Finished T/C March 2009. Finished #16 Herceptin Sept. 09. AI's and Tamoxifen made me sick. Began natural Tamoxifen which is Quercetin, I3C and a combo of other supplements. I am also a DES Daughter. There is now a link between DES exposure in utero and breast cancer!
It can work through means beyond ER+ and it can cross the blood/brain barrier. Have your doc investigate selenium supplements to help the Tamoxifen and Metformin to regulate blood sugar and prevent endometrial cancer, a rare side effect of Tamoxifen.
Mol Nutr Food Res. 2009 Nov 10. [Epub ahead of print] Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF-7 tumor growth through estrogen receptor- and growth factor-signaling pathways.
Saggar JK, Chen J, Corey P, Thompson LU.
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels, and potential mechanisms of action. In a 2x2 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER-mediated (ER-alpha, ER-beta, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor-mediated (epidermal growth factor receptor, human epidermal growth factor receptor-2, insulin-like growth factor receptor-1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and angiogenesis (vascular endothelial growth factor). alone. All treatments reduced the growth of TAM-treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatmentSDG and FO reduced the growth of TAM-treated tumors but FO was more effective. The mechanisms involve both the ER- and growth factor-signaling pathways.
PMID: 19904759 [PubMed - as supplied by publisher]
Asian Pac J Cancer Prev. 2009 Oct-Dec;10(4):609-12. Tamoxifen use in Indian women--adverse effects revisited.
Ashraf M, Biswas J, Majumdar S, Nayak S, Alam N, Mukherjee KK, Gupta S.
Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata, India. ashraf_qz@yahoo.co.in
BACKGROUND: Tamoxifen is generally considered a safe drug for Indian women with breast cancer. Indian women seem to tolerate tamoxifen therapy better than western women, but there are no data regarding safety and local adverse effect profiles in typical Indian populations. METHODS AND RESULTS: A total of 3,000 case records of patients who had received tamoxifen daily for any period of time, between January 1988 and December 2007, were identified for study. Hot flashes were reported by 800 (26%), mild vaginal dryness by 450 (15%) and vaginal discharge by 300 (10%), with vaginal bleeding experienced by 40 (1.3%) patients. A total of 1,100 (36.6%) asymptomatic patients had a thickened endometrium(defined as >8mm in thickness) on ultrasonography. Endometrial curettage was performed in all of these. None of the patients developed endometrial carcinoma. Fatty infiltration of liver was found in 1,440 (48%) patients with a mean time interval for development of 7 months (range 6-30 months). CONCLUSIONS: Fatty infiltration of liver is found in almost half of the Eastern Indian women who receive tamoxifen. Increased endometrial thickness, which remains asymptomatic, was documented in more than one third of patients on ultrasound examination. Tamoxifen seems to have a negligible potential for causation of uterine malignancies in eastern Indian women. Rates of hysterectomies in Indian patients on tamoxifen are substantially lower than those of western patients on tamoxifen.
Here is a screen shot that shows the impact of aspirin on endoxifen (this is the chemical tamoxifen is converted to that actually prevents breast cancer recurrence). Half of the endoxifen is converted by a liver enzyme called UGT2B7 to something our body can than eliminate. Aspirin is a moderate inhibitor of UGT2B7 so it keeps the endoxifen in the body longer before it is eliminated. This could actually be beneficial for 2D6 IMs as other threads have pointed out. Of course, studies would have to be done to confirm this. There is no current medical information that indicates any reason to be concerned about reducing tamoxifen effectiveness with aspirin.
I recently done my MBA and now days I want to do some online Microsoft certifications and I Found this online notes is a best helping source to get online accurate information which is more helpful for my preparation.
This article has been 
300 mm3, mice received 6 weeks’ oral vehicle (control), X (d1–14 q21d) at MTD (539 mg/kg) or 2/3 MTD, and/or TAM at 100 or 30 mg/kg/d. We also analyzed impact of 5-FU and doxifluridine (5'-DFUR, an intermediate of X) + TAM on estrogen receptor (ER) signals in an in-vitro culture system. ER signals were monitored by expression of green fluorescent protein (GFP) in MCF-7 BC cells transfected with the estrogen-responsive element (ERE)-GFP gene (MCF-7-E10). GFP expression was induced in MCF-7-E10 cells in the presence of estradiol at 3 pM or BC tissue supernatant. Results: X at 2/3 MTD + TAM 30 mg/kg were significantly more active than the highest dose of X or TAM alone. Tumor TP concentrations were significantly higher in TAM- than vehicle-treated mice. In the ER signal system, GFP expression of MCF-7-E10 was reduced by 4-hydroxytamoxifen (4-OHT, active form of TAM) at 0.01 and 0.1 nM. When added to 4-OHT, 5-FU 0.3–30 µM or 5'-DFUR 3–10 µM reduced GFP expression more than either agent alone. In vitro, 5-FU and 5'-DFUR inhibited proliferation of MCF-7-E10 cells regardless of 4-OHT. Additive effects could not be confirmed as 4-OHT alone showed only marginal anti- proliferative activity at 0.01–0.1 nM. Conclusion: X and TAM are not antagonistic in this model. TAM may augment X activity via TP upregulation in BC tissues. TAM and X intermediates showed no clear antagonism in vitro in an ER signal system. All-oral X + TAM merits evaluation as combination therapy in breast cancer.
WEDNESDAY 12 NOVEMBER 2008
Linear Mode
According to the study, tamoxifen-resistant breast cancer cells display few of the alpha estrogen receptors that the drug is designed to bind with and inhibit. Instead, they display many more gamma estrogen-related receptors, which tamoxifen appears to activate.
They also tracked how, as tamoxifen resistance increases, breast cancer cells gradually lose their alpha receptors while gaining more estrogen-related gamma receptors.
The study was just published in the November 1st issue of the journal Cancer Research. It gives a clearer understanding of the importance of the gamma estrogen-related receptor in breast cancer. This receptor had not been viewed with much importance in any type of breast cancer. All that was known was that there were more of these receptors in breast cancer than in normal breast tissue.
The findings could also help to explain why invasive lobular carcinoma, the subtype studied, may not respond as well to tamoxifen as other breast cancer subtypes. The study may give scientists a good first step toward clarifying the role that tamoxifen resistance apparently plays in treatment of invasive lobular cancer.
It is why a breast cancer patient should test the tumor first by submitting the surgical specimen to an assay lab to tell if Tamoxifen would work on the receptors on the surface of breast cancer cells, or something else.