Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S77-88. Deciphering antihormone-induced compensatory mechanisms in breast cancer and their therapeutic implications.
Breast cancer inhibition by antihormones is rarely complete, and our studies using responsive models reveal the remarkable flexibility of breast cancer cells in recruiting alternative signalling to limit maximal anti-tumour effects of oestrogen receptor alpha (ER) blockade. The recruited mechanism involves antihormone-induced expression of oestrogen-repressed signalling genes. For example, epidermal growth factor receptor gene (EGFR) is induced by antioestrogens and maintains residual kinase and ER phosphorylation, cell survival genes, and thereby allows incomplete antihormone response and emergence of resistance. Microarrays are revealing the breadth of antihormone-induced genes that may attenuate growth inhibition, including NFkappaB, Bag1, 14-3-3zeta and tyrosine kinases, such as HER2 and Lyn. Three concepts are emerging: first, some genes are induced exclusively by antioestrogens, while others extend to oestrogen deprivation; secondly, some are transiently induced, while others persist into resistance; finally, some confer additional adverse features when tumour cells are in an appropriate context. Among the latter is CD59 whose antioestrogen induction may permit evasion of immune surveillance in vivo. Also, induction of pro-invasive genes (including NFkappaB, RhoE and delta-catenin) may underlie our findings that antioestrogens can markedly stimulate migratory behaviour when tumour intercellular contacts are compromised. Based on our promising studies selectively inhibiting EGFR (gefitinib), NFkappaB (parthenolide) or CD59 (neutralising antibody) together with antioestrogens, we propose that co-targeting strategies could markedly improve anti-tumour activity (notably enhancing cell kill) during the antihormone-responsive phase. Furthermore, subverting those induced signalling genes that are retained into resistance (e.g. EGFR, NFkappaB, HER2) may prove valuable in this state. Alongside future deciphering and targeting of genes underlying antioestrogen-promoted invasiveness, embracing of intelligent combination strategies could significantly extend patient survival.
PMID: 17259561 [PubMed - indexed for MEDLINE]Free Article
Breast Cancer Res. 2008;10(6):R103. Epub 2008 Dec 4. Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells.
INTRODUCTION: Anti-oestrogens have been the mainstay of therapy in patients with oestrogen-receptor (ER) positive breast cancer and have provided significant improvements in survival. However, their benefits are limited by tumour recurrence in a significant proportion of initially drug-responsive breast cancer patients because of acquired anti-oestrogen resistance. Relapse on such therapies clinically presents as local and/or regional recurrences, frequently with distant metastases, and the prognosis for these patients is poor. The selective ER modulator, tamoxifen, classically exerts gene inhibitory effects during the drug-responsive phase in ER-positive breast cancer cells. Paradoxically, this drug is also able to induce the expression of genes, which in the appropriate cell context may contribute to an adverse cell phenotype. Here we have investigated the effects of tamoxifen and fulvestrant treatment on invasive signalling and compared this with the direct effects of oestrogen withdrawal to mimic the action of aromatase inhibitors. METHODS: The effect of oestrogen and 4-hydroxy-tamoxifen on the invasive capacity of endocrine-sensitive MCF-7 cells, in the presence or absence of functional E-cadherin, was determined by Matrigel invasion assays. Studies also monitored the impact of oestrogen withdrawal or treatment with fulvestrant on cell invasion. Western blotting using phospho-specific antibodies was performed to ascertain changes in invasive signalling in response to the two anti-oestrogens versus both oestradiol treatment and withdrawal. RESULTS: To the best of our knowledge, we report for the first time that tamoxifen can promote an invasive phenotype in ER-positive breast cancer cells under conditions of poor cell-cell contact and suggest a role for Src kinase and associated pro-invasive genes in this process. Our studies revealed that although this adverse effect is also apparent for further classes of anti-oestrogens, exemplified by the steroidal agent fulvestrant, it is absent during oestrogen withdrawal. CONCLUSIONS: These data highlight a previously unreported effect of tamoxifen (and potentially further anti-oestrogens), that such agents appear able to induce breast cancer cell invasion in a specific context (absence of good cell-cell contacts), where these findings may have major clinical implications for those patients with tumours that have inherently poor intercellular adhesion. In such patients oestrogen deprivation with aromatase inhibitors may be more appropriate.
PMID: 19055788 [PubMed - indexed for MEDLINE]PMCID: PMC2656899Free PMC Article
Matthew Ellis Siteman Cancer Center, Washington University, St. Louis, Missouri, USA
Correspondence: Matthew Ellis, M.D., Ph.D., F.R.C.P., Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, Division of Oncology, St. Louis, Missouri 63110, USA. Telephone: 314-362-8866; Fax: 314-362-7086; e-mail: mellis@im.wustl.edu
Endocrine therapy is the most effective systemic treatment forpatients with hormone-receptor-positive (HR+) breast cancer.Unfortunately, efficacy is often limited by the onset of resistance,which is almost inevitable for patients with advanced disease.Several patterns of endocrine resistance are recognizable clinically,including: A) tumors that are inherently insensitive to allattempts at estrogen receptor (ER) targeting despite expressionof ER (pan-endocrine therapy resistance); B) tumors that areestrogen dependent but resistant to one or more specific endocrinetherapies (agent-selective resistance); and C) tumors that initiallyrespond but subsequently progress (acquired resistance). Currentinsights into the molecular basis for these resistance patternsare rudimentary, but are most clearly illuminated by investigationsthat focus on the crosstalk between the ErbB or HER peptidegrowth factor family and the ER. The data are sufficiently compellingto be addressed by ongoing clinical trials that examine combinationsof endocrine agents and either trastuzumab (Herceptin®;Genentech, Inc.; South San Francisco, CA) or ErbB-specific tyrosinekinase (TK) inhibitors. Preliminary data from a small "proofof concept" phase II study of letrozole (Femara®; NovartisPharmaceuticals Corporation; East Hanover, NJ) and trastuzumabdemonstrated durable responses despite tamoxifen (Nolvadex®;AstraZeneca Pharmaceuticals; Wilmington, DE) resistance. Efficacywas variable, however, despite the selection of patients onthe basis of ER and ErbB-2 coexpression. Complicating mattersfurther, resistance often occurs in the absence of any evidencefor ErbB TK family member expression. In the absence of a cleartarget, common downstream signal transduction proteins thatare known to intersect with the ER pathway can be inhibitedto address resistance, including G proteins with farnesyltransferaseinhibitors and molecular target of rapamycin (mTOR) with rapamycinanalogues. With a number of phase III clinical trials now underway, major advances in the endocrine treatment of advanced diseaseare possible.
Breast Cancer Res Treat. 2010 Feb 5. [Epub ahead of print] Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells.
Zakikhani M, Blouin MJ, Piura E, Pollak MN.
Department of Oncology, McGill University, Montreal, QC, Canada.
Rapamycin and its analogues inhibit mTOR, which leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5'- monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions, in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. As mTOR inhibition by rapamycin is associated with attenuation of negative feedback to IRS-1, rapamycin is known to increase activation of AKT, which may reduce its anti-neoplastic activity. We observed that metformin exposure decreases AKT activation, an action opposite to that of rapamycin. We show that metformin (but not rapamycin) exposure leads to increased phosphorylation of IRS-1 at Ser(789), a site previously reported to inhibit downstream signaling and to be an AMPK substrate phosphorylated under conditions of cellular energy depletion. siRNA methods confirmed that reduction of AMPK levels attenuates both the IRS-1 Ser(789) phosphorylation and the inhibition of AKT activation associated with metformin exposure. Although both rapamycin and metformin inhibit mTOR (the former directly and the latter through AMPK signaling), our results demonstrate previously unrecognized differences between these agents. The data are consistent with the observation that maximal induction of apoptosis and inhibition of proliferation are greater for metformin than rapamycin.
PMID: 20135346
SABC 2009
67. Targeting Aldose Reductase: A Novel Strategy in Treating Endocrine Resistance Using Combination Therapy
Treating estrogen receptor-positive breast cancer tumors with a combination of fidarestat (an inhibitor of aldose reductase enzyme) and letrozole (an aromatase inhibitor) could delay or stop tumor resistance to endocrine therapy, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.
"Single agents are less effective," said Rajeshwar Rao Tekmal, Ph.D., professor of obstetrics and gynecology at the University of Texas Health Science Center at San Antonio. "Many tumors develop resistance, so this combination approach could prolong that window when endocrine therapy is effective."
About two-thirds of breast cancer tumors initially are hormone sensitive or estrogen receptor-positive and respond well to endocrine therapy. However, close to half of those tumors develop resistance to endocrine therapy, said Tekmal.
In this preclinical study, researchers treated estrogen receptor-positive tumors already resistant to letrozole with letrozole and fidarestat. As an inhibitor of aldose reductase enzyme, fidarestat blocks the metabolism of glucose in cancer cells. Together, the combination effectively re-sensitized the cells to letrozole, allowing for effective endocrine therapy and more cell death.
Researchers believe increased glucose metabolism (polyol accumulation) contributes to oxidative stress, which, in turn, could alter intracellular signalling by affecting the regulation of protein kinases that are known to be involved in therapy resistance. Blocking the path of glucose metabolism may help to restore sensitivity to endocrine therapies or it may stop or delay the development resistance endocrine therapies in first place.
While this is a preclinical study, Tekmal believes it could lead to future drug treatments that will make endocrine therapy more effective for longer periods of time.
"This is a very promising study showing that combination treatments seem to work on resistance and re-sensitizing tumors that are resistant to endocrine therapies," he said.
Listen to a recording of the teleconference:
Download* the mp3 of the teleconference (13.2 MB, 58 minutes and 04 seconds)
Does Glucose issue mean Metformin (also mTOR inhib) helpful?
http://www.patentstorm.us/patents/68...scription.html
Among the natural compounds, flavonoid compounds such as quercetin, quercetrin, naringinin and hesperidin are reported to be useful and potent aldose reductase inhibitors (Aida, K., Tawata, M., Shindo, H., Onaya, T., Sasaki H., Yamaguchi T., Chin, M., Mitsuhashi. Planta Med, 56 (1990) 254-258).
Vitamin C: an aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus
J. J. Cunningham, P. L. Mearkle and R. G. Brown
Department of Nutrition, University of Massachusetts, Amherst 01003-1420.
OBJECTIVE: Diabetic hyperglycemia promotes sorbitol production from glucose via aldose reductase. Since the intracellular accumulation of sorbitol, or its sequelae, are postulated to contribute to the progression of chronic diabetic complications, aldose reductase inhibitors (ARI) offer therapeutic promise. Others have shown that vitamin C at pharmacologic doses decreases erythrocyte (RBC) sorbitol. We examined whether smaller, physiologic doses of vitamin C were also effective in individuals with insulin-dependent diabetes mellitus (IDDM) and whether vitamin C was an ARI in vitro. METHODS: Vitamin C supplements (100 or 600 mg) were taken daily for 58 days by young adults with IDDM and nondiabetic adults in an otherwise free-living design. Diabetic control was monitored by fasting plasma glucose, glycosylated hemoglobin, and glycosuria and was moderate to poor throughout the study. RBC sorbitol was measured at baseline and again at 30 and 58 days. Three-day dietary records and 24-hour urine collections were performed for each sampling day. RESULTS: RBC sorbitol levels were significantly elevated in IDDMs, on average doubled, despite their more than adequate dietary intakes of vitamin C and normal plasma concentrations. Vitamin C supplementation at either dose normalized the RBC sorbitol in IDDMs within 30 days. This correction of sorbitol accumulation was independent of changes in diabetic control. Furthermore, our in vitro studies show that ascorbic acid inhibited aldose reductase activity. CONCLUSIONS: Vitamin C supplementation is effective in reducing sorbitol accumulation in the erythrocytes of diabetics. Given its tissue distribution and low toxicity, we suggest a superiority for vitamin C over pharmaceutic ARIs.
J. J. Cunningham Micronutrients as Nutriceutical Interventions in Diabetes Mellitus
J. Am. Coll. Nutr., February 1, 1998; 17(1): 7 - 10. [Abstract][Full Text][PDF]
By Julie Steenhuysen
CHICAGO, Dec 11 (Reuters) - U.S. researchers may have found a way to overcome resistance to hormone-blocking breast cancer drugs, extending the life of treatments that keep the disease in check.
They said the drug Nexavar or sorafenib, made by German drugmaker Bayer (BAYGn.DE) and its development partner Onyx Pharmaceuticals (ONXX.O), helped re-sensitize breast cancer to treatment with aromatase inhibitors, drugs given to post-menopausal women with hormone-sensitive breast cancers.
"Hormone-receptor positive breast cancers eventually become resistant to hormonal therapy," said Dr. Claudine Isaacs of Georgetown University in Washington, who presented her findings at the American Association for Cancer Research's San Antonio Breast Cancer Symposium.
"There has been a great deal of interest in trying to figure out how we might overcome that resistance or stop the cancer cells from figuring out how to circumvent that hormonal therapy," Isaacs said in a telephone interview.
She said Nexavar, a drug approved for liver and kidney cancer, acts on a lot of cancer-related genes and it also acts to inhibit new blood vessels from forming.
The researchers studied the drug in 35 post-menopausal women with advanced breast cancer resistant to treatment with aromatase inhibitors.
Women in the trial, funded with a grant by Bayer, continued to take the aromatase inhibitor, but they also took Nexavar.
"These women all had disease progression. Twenty-three percent of the women in the study had a clinical benefit from it. It means they either had shrinkage of their tumors or it stayed stable," Isaacs said.
Isaacs said the finding suggests the drug somehow circumvents the mechanism used by the cancer to resist the effects of the aromatase inhibitors. "It puts the brakes on it so it didn't grow for at least six months," she said.
The treatment was not without side effects. Many women in the study developed a rash called hand-foot syndrome, which causes redness, peeling and some tenderness on the palms of the hands and soles of the feet. It also caused elevated blood pressure in 11 percent of the women, but Isaacs this could be overcome by putting women on blood pressure drugs before taking Nexavar. She said the findings were strong enough to inspire the drug companies to start a large, late-stage study to see if it has a significant benefit for women.
Aromatase inhibitors include anastrozole, made by AstraZeneca (AZN.L) under the brand name Arimidex, and exemestane, made by Pfizer Inc (PFE.N), under the brand name Aromasin.
LINK Potential new therapy to re-sensitize breast cancer (Nexavar/Sorafenib)
Clin Cancer Res. 2010 Feb 23. [Epub ahead of print] Lapatinib Restores Hormone Sensitivity with Differential Effects on Estrogen Receptor Signaling in Cell Models of Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer with Acquired Endocrine Resistance.
Leary AF, Drury S, Detre S, Pancholi S, Lykkesfeldt AE, Martin LA, Dowsett M, Johnston SR.
Authors' Affiliations: Royal Marsden Hospital and Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom; and Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
PURPOSE: Acquired endocrine resistance in estrogen receptor (ER)alpha+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer has been associated with modest adaptive increases in HER2, although exactly how aberrant HER2 signaling affects the ERalpha pathway is poorly understood. We investigated (a) whether the epidermal growth factor receptor/HER2 inhibitor lapatinib could restore endocrine responsiveness in cell models of acquired endocrine resistance with modest increases in HER2, and (b) the nature of ERalpha-HER2 cross-talk in this process. Methods: Combination growth studies, ERalpha transcription, immunoblot, and gene expression assays were conducted in two models of acquired resistance to (a) estrogen deprivation (long-term estrogen-deprived cells) and (b) tamoxifen (long-term tamoxifen-treated cells), and in hormone sensitive controls. Changes in ERalpha, PgR, and HER2 were assessed in samples from patients treated with tamoxifen. RESULTS: Both cell models of acquired endocrine resistance showed modest adaptive upregulation in HER2, and lapatinib restored endocrine sensitivity in both. The effect of lapatinib on ERalpha signaling varied markedly depending on the nature of the HER2/ERalpha cross-talk. In long-term estrogen-deprived cells characterized by enhanced ERalpha function, lapatinib suppressed ERalpha genomic activity (as measured by pERSer118, ERalpha transcriptional activity, and PGR gene expression). In contrast, in long-term tamoxifen-treated cells with reduced ERalpha activation, lapatinib reactivated ERalpha genomic function. Twenty percent of tamoxifen-resistant patients relapsed with modest increases in HER2 and either suppressed or enhanced ERalpha/PgR expression. CONCLUSIONS: Aberrant GFR signaling can augment or suppress ERalpha function. Regardless, interrupting the HER2/ERalpha cross-talk with lapatinib can restore endocrine sensitivity and should be investigated as a therapeutic strategy in combination with endocrine therapy in ERalpha+/HER2- patients with acquired endocrine resistance. Clin Cancer Res; 16(5); 1486-97.
PMID: 20179226 [PubMed - as supplied by publisher]
Clin Cancer Res. 2010 Feb 23. [Epub ahead of print] Does Lapatinib Work against HER2-negative Breast Cancers?
Mayer IA, Arteaga CL.
Authors' Affiliations: Departments of Medicine, Cancer Biology, and Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Aberrant growth factor receptor signaling can augment or suppress estrogen receptor (ER) function in hormone-dependent breast cancer cells and lead to escape from anti-estrogen therapy. Interruption of HER2/ER cross-talk with lapatinib can restore sensitivity to anti-estrogens and thus, should be investigated in combination with endocrine therapy in patients with ER+/HER2-negative breast cancers. Clin Cancer Res; 16(5); 1355-7.
PMID: 20179241 [PubMed - as supplied by publisher]
Low Forms of Cyclin E Reduce Breast Cancer Drug's Effectiveness
ScienceDaily (Feb. 9, 2010) — Overexpression of low-molecular-weight (LMW-E) forms of the protein cyclin E renders the aromatase inhibitor letrozole ineffective among women with estrogen-receptor-positive (ER+) breast cancers, researchers from The University of Texas M. D. Anderson Cancer Center report in Clinical Cancer Research.
The M. D. Anderson research, led by Khandan Keyomarsi, Ph.D., professor in M. D. Anderson's Department of Experimental Radiation Oncology and the Hubert L. and Olive Stringer Professor in Medical Oncology, found evidence that women whose cancers express the LMW-E are more likely to develop resistance to letrozole. However, their research also showed that treating breast cancer cells with a cyclin-dependent kinase 2 (CDK2) inhibitor can reverse letrozole resistance.
Cyclin E is one of the proteins that regulates the cell cycle, influencing how rapidly a cell passes through the four phases and divides. In tumor cells, cyclin E is converted to low-molecular weight forms, an event that does not occur in normal cells. High levels of LMW-E accelerate the cell's transition through the G1phase, an important checkpoint that can arrest the cell cycle if DNA damage is detected. Elevated levels of LMW-E have been linked to uncontrolled cell proliferation and a poor outcome in breast cancer patients. Outwitting Drug Resistance
Keyomarsi estimated that approximately 70 percent of all breast cancer patients are estrogen receptor positive (ER+), of which a large percentage are post-menopausal, and would thereby be a candidate to receive an aromatase inhibitor as maintenance therapy. Aromatase inhibitors can reduce the risk of early metastasis among postmenopausal women with ER+ breast cancer. However, not every patient responds to aromatase inhibitors, and those who do will develop resistance to the drugs over time, explained Keyomarsi. Understanding the mechanisms behind this resistance has been a long-standing goal in breast cancer research. The M. D. Anderson team hypothesized that ER+ breast cancer patients whose tumors express the LMW forms of cyclin E would be less responsive to treatment with an aromatase inhibitor. To test their hypothesis, the researchers exposed aromatase-overexpressing MCF-7/Ac1 breast cancer cells to the full-length form of cyclin E or to the LMW-E forms ("low forms").
"We found that we could negate the growth inhibitory effects of letrozole with the low forms of cyclin E but not with the wild-type cyclin E," said Keyomarsi, the study's senior author. "The mechanism behind this is that the low forms of cyclin E increase the activity of the cyclin E complex, and this complex is what mediates the negative effects."
After confirming that the LMW forms of cyclin E suppress the anti-proliferative effects of letrozole, the researchers examined whether a CDK2 inhibitor could reverse the drug resistance in the unresponsive breast cancer cells. "We challenged the aromatase-overexpressing cells with either the wild-type or the low forms of cyclin E and then treated them with the CDK2 inhibitor roscovitine," Keyomarsi said. "When we did that, we could kill all the cells." The researchers also looked back at the results of another ongoing study from their group in which 128 ER+ breast cancer patients were treated with an aromatase inhibitor. "Of those, 100 expressed normal levels of wild-type cyclin E, and 28 overexpressed the low forms," Keyomarsi said. "When we looked at recurrence, three of the hundred with wild-type cyclin E had experienced a recurrence compared to four of the twenty-eight with the low forms. That in itself tells us there is a huge difference between the two groups of patients based on the pattern of expression of normal versus low forms of cyclin E." Of the seven patients who had a recurrence, six had high levels of cyclin E activity. Keyomarsi noted that these patients can be treated with a CDK2 inhibitor, which is now clinically available.
"I believe that in the very near future we will be able to take advantage of the knowledge we now have about the low forms of cyclin E, and identify the patients who have these forms and devise a personalized treatment," Keyomarsi added.
This research was supported by National Institutes of Health grant CA87458 and National Cancer Institute grant P50CA116199, as well as funds from the Clayton Foundation.
Keyomarsi's co-authors on the all-M. D. Anderson study include: Said Akli, Ph.D., Tuyen Bui, Anna Biernacka, M.D. all of the Department of Experimental Radiation Oncology; Kelly K. Hunt, M.D.; and Hannah Wingate, Ph.D., Department of Surgical Oncology; Stacy Moulder, M.D., Department of Breast Medical Oncology; and Susan L. Tucker, Ph.D., Department of Bioinformatics and Computational Biology.
PLoS One. 2010 Jan 6;5(1):e8604. Co-inhibition of BCL-W and BCL2 restores antiestrogen sensitivity through BECN1 and promotes an autophagy-associated necrosis.
Crawford AC, Riggins RB, Shajahan AN, Zwart A, Clarke R.
Lombardi Comprehensive Cancer Center and Department of Oncology, School of Medicine, Georgetown University, Washington, District of Columbia, United States of America.
BCL2 family members affect cell fate decisions in breast cancer but the role of BCL-W (BCL2L2) is unknown. We now show the integrated roles of the antiapoptotic BCL-W and BCL2 in affecting responsiveness to the antiestrogen ICI 182,780 (ICI; Fulvestrant Faslodex), using both molecular (siRNA; shRNA) and pharmacologic (YC137) approaches in three breast cancer variants; MCF-7/LCC1 (ICI sensitive), MCF-7/LCC9 (ICI resistant), and LY2 (ICI resistant). YC137 inhibits BCL-W and BCL2 and restores ICI sensitivity in resistant cells. Co-inhibition of BCL-W and BCL2 is both necessary and sufficient to restore sensitivity to ICI, and explains mechanistically the action of YC137. These data implicate functional cooperation and/or redundancy in signaling between BCL-W and BCL2, and suggest that broad BCL2 family member inhibitors will have greater therapeutic value than targeting only individual proteins. Whereas ICI sensitive MCF-7/LCC1 cells undergo increased apoptosis in response to ICI following BCL-W+/-BCL2 co-inhibition, the consequent resensitization of resistant MCF-7/LCC9 and LY2 cells reflects increases in autophagy (LC3 cleavage; p62/SQSTM1 expression) and necrosis but not apoptosis or cell cycle arrest. Thus, de novo sensitive cells and resensitized resistant cells die through different mechanisms. Following BCL-W+BCL2 co-inhibition, suppression of functional autophagy by 3-methyladenine or BECN1 shRNA reduces ICI-induced necrosis but restores the ability of resistant cells to die through apoptosis. These data demonstrate the plasticity of cell fate mechanisms in breast cancer cells in the context of antiestrogen responsiveness. Restoration of ICI sensitivity in resistant cells appears to occur through an increase in autophagy-associated necrosis. BCL-W, BCL2, and BECN1 integrate important functions in determining antiestrogen responsiveness, and the presence of functional autophagy may influence the balance between apoptosis and necrosis.
PMID: 20062536 [PubMed - in process]
Breast Cancer Res Treat. 2009 Nov 27. [Epub ahead of print] ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole.
Smollich M, Götte M, Fischgräbe J, Macedo LF, Brodie A, Chen S, Radke I, Kiesel L, Wülfing P.
Department of Obstetrics and Gynecology, University Hospital of Münster, Albert-Schweitzer-Str. 33, 48129, Munster, Germany.
Endothelin-1 (ET-1) and endothelin A receptor (ETAR) contribute to the development and progression of breast carcinomas by modulating cell proliferation, angiogenesis, and anti-apoptosis. We investigated antitumoral effects of the specific ETAR antagonist ZD4054 in breast cancer cells and xenografts, and assessed antitumoral efficacy of the combinations of ZD4054 with aromatase inhibitors and fulvestrant. Gene expression changes were assessed by quantitative real-time PCR. Cell proliferation was measured using alamarBlue((R)); migration and invasion assays were performed using modified Boyden chambers. Evaluating the antitumoral efficacy of ZD4054 in vivo, different breast cancer models were employed using nude mice xenografts. ZD4054 reduced ET-1 and ETAR expression in MCF-7, MDA-MB-231, and MDA-MB-468 breast cancer cells in a concentration-dependent manner. ZD4054 inhibited invasion by up to 37.1% (P = 0.022). Combinations of ZD4054 with either anastrozole or letrozole produced significant reductions in migration of aromatase-overexpressing MCF-7aro cells (P < 0.05). Combination of ZD4054 with fulvestrant reduced MCF-7 cell migration and invasion by 36.0% (P = 0.027) and 56.7% (P < 0.001), respectively, with effects significantly exceeding those seen with either compound alone. Regarding tumor volume reduction in vivo, ZD4054 (10 mg/kg) was equipotent to fulvestrant (200 mg/kg) and exhibited additive effects with anastrozole (0.5 mg/kg). These data are the first indicating that selective ETAR antagonism by ZD4054 displays antitumoral activity on breast cancer cells in vitro and in vivo. Our data strongly support a rationale for the clinical use of ZD4054 in combination with endocrine therapies.
PMID: 19943105 [PubMed - as supplied by publisher]
J Endocrinol. 2004 Nov;183(2):395-404. All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor beta to stimulate apoptosis in MCF-7 breast cancer cells.
Danforth DN Jr.
Surgery Branch, National Cancer Institute, National Institutes of Health, Bldg. 10/Rm 2B42, Bethesda, Maryland 20892, USA. David_Danforth@nih.gov The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throughout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis. The negative growth factor-transforming growth factor beta (TGFbeta) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGFbeta1 secretion over 72 h. TGFbeta1 alone had no apoptotic effects on these cells; however, TGFbeta1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGFbeta1+AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGFbeta antibody did not block down-regulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGFbeta, although TGFbeta may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.
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 Res. 2010 Feb 23. [Epub ahead of print] FGFR1 Amplification Drives Endocrine Therapy Resistance and Is a Therapeutic Target in Breast Cancer.
Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A.
Authors' Affiliations: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research; Breast Unit, Royal Marsden Hospital; Breakthrough Breast Cancer Research Unit, King's College London School of Medicine, Guy's Hospital, London, United Kingdom. Amplification of fibroblast growth factor receptor 1 (FGFR1) occurs in approximately 10% of breast cancers and is associated with poor prognosis. However, it is uncertain whether overexpression of FGFR1 is causally linked to the poor prognosis of amplified cancers. Here, we show that FGFR1 overexpression is robustly associated with FGFR1 amplification in two independent series of breast cancers. Breast cancer cell lines with FGFR1 overexpression and amplification show enhanced ligand-dependent signaling, with increased activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase-AKT signaling pathways in response to FGF2, but also show basal ligand-independent signaling, and are dependent on FGFR signaling for anchorage-independent growth. FGFR1-amplified cell lines show resistance to 4-hydroxytamoxifen, which is reversed by small interfering RNA silencing of FGFR1, suggesting that FGFR1 overexpression also promotes endocrine therapy resistance. FGFR1 signaling suppresses progesterone receptor (PR) expression in vitro, and likewise, amplified cancers are frequently PR negative, identifying a potential biomarker for FGFR1 activity. Furthermore, we show that amplified cancers have a high proliferative rate assessed by Ki67 staining and that FGFR1 amplification is found in 16% to 27% of luminal B-type breast cancers. Our data suggest that amplification and overexpression of FGFR1 may be a major contributor to poor prognosis in luminal-type breast cancers, driving anchorage-independent proliferation and endocrine therapy resistance. Cancer Res; 70(5); 2085-94.
PMID: 20179196 [PubMed - as supplied by publisher]
At a concentration of 1 μM, resveratrol significantly inhibited the VEGF-induced
PAE/VEGFR-2 endothelial cell migration (Fig. 1F). These data demonstrate that resveratrol inhibits both FGF- and VEGF-receptor-mediated endothelial cell growth and chemotaxis.
Threaded Mode