(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.
Quote:
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).
<
Quote:
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)
<
Quote:
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.
<
Quote:
In fact, in four tumors that did not overexpress HER2, pHER2 was nevertheless found to be activated.
<
Quote:
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.
<
Quote:
/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."
This article has been 
Threaded Mode