Fulvestrant (ICI 182,780) sensitizes breast cancer cells expressing estrogen receptor α to vinblastine and vinorelbine
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Cumulative data suggest that some chemotherapeutic agents may be less effective in estrogen receptor α positive (ER+) breast tumors than ER negative (ER−) tumors, which has raised a clinically relevant question as to how to reverse this ER-mediated chemoresistance in ER+ breast tumors. This study is to investigate the possible influence of estrogen receptor α (ERα) on the therapeutic effects of vinblastine and vinorelbine on breast cancer cells and explore whether combination of anti-estrogen agent fulvestrant (ICI 182, 780) may enhance the sensitivity of ERα+ cells to these chemotherapeutic agents. Through comparing ER+ with ER− human breast tumor cells or through stable transfection of an ERα expression vector into ER negative human breast cancer BCap37 cells, a series of assays were applied to determine the sensitivity of ER+ and ER− breast tumor cells to vinblastine and vinorelbine in the presence or absence of 17-β-estradiol and/or fulvestrant. 17-β-Estradiol showed no effect on the sensitivity of ER− MDA-MB-468 and BCap37 cells to the treatment of vincristine or vinblastine, but it significantly reduced the sensitivity of ER+ T47D cells and BCap37 cells expressing ERα to the two drugs mentioned. Further analyses show that ERα has little effect on vinca alkaloids-induced mitotic arrest, but dramatically affects their ability to induce tumor cell apoptosis. Moreover, through a series of assays, we also demonstrated that the combination of fulvestrant, a selective ER down-regulator, could reverse the resistance of ER+ breast tumor cells to vinca alkaloids and even produce synergistic effects. The findings obtained from this study have provided important evidence that expression and subsequent activation of ERα are associated with resistance of breast cancer cells to vinca alkaloids. This study also suggested that the combination of anti-estrogen agents, such as fulvestrant, might be a novel strategy to reverse ER-mediated chemoresistance or sensitize ER+ breast tumors to vinca alkaloids and possibly other chemotherapeutic agents.
KeywordsFulvestrant Estrogen receptor Breast cancer Vinorelbine
This study was supported by the research grant (ZDST 2008C14079) from Department of Science and Technology of Zhejiang Province and NIH Grant CA92880 (to Fan W).
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