Program of Innovative Cancer Therapeutics, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China.
Breast Cancer Res Treat. 2010 Jun;121(2):335-45. doi: 10.1007/s10549-009-0472-4. Epub 2009 Jul 22.
Cumulative data suggest that some chemotherapeutic agents may be less effective in estrogen receptor alpha 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 alpha (ERalpha) 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 ERalpha+ cells to these chemotherapeutic agents. Through comparing ER+ with ER- human breast tumor cells or through stable transfection of an ERalpha 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-beta-estradiol and/or fulvestrant. 17-beta-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 ERalpha to the two drugs mentioned. Further analyses show that ERalpha 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 ERalpha 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.
累积的数据表明，一些化疗药物在雌激素受体阳性（ER+）乳腺癌肿瘤中的疗效可能不如雌激素受体阴性（ER-）肿瘤，这就提出了一个临床上相关的问题，即如何逆转 ER+乳腺癌肿瘤中的这种 ER 介导的化疗耐药性。本研究旨在探讨雌激素受体α（ERα）对长春碱和长春瑞滨治疗乳腺癌细胞疗效的可能影响，并探索抗雌激素药物氟维司群（ICI 182,780）是否可以增强 ERα+细胞对这些化疗药物的敏感性。通过比较 ER+与 ER-人乳腺癌细胞，或通过 ER 阴性人乳腺癌 BCap37 细胞稳定转染 ERα表达载体，应用一系列检测方法来确定 ER+和 ER-乳腺癌细胞在 17-β-雌二醇和/或氟维司群存在或不存在的情况下对长春碱和长春瑞滨的敏感性。17-β-雌二醇对 ER-MDA-MB-468 和 BCap37 细胞对长春新碱或长春碱治疗的敏感性没有影响，但它显著降低了 ER+T47D 细胞和表达 ERα的 BCap37 细胞对这两种药物的敏感性。进一步的分析表明，ERα对长春新碱诱导的有丝分裂阻滞几乎没有影响，但对它们诱导肿瘤细胞凋亡的能力有显著影响。此外，通过一系列实验，我们还证明了选择性 ER 下调剂氟维司群的联合应用可以逆转 ER+乳腺癌细胞对长春碱类药物的耐药性，甚至产生协同作用。本研究结果为雌激素受体α的表达和随后的激活与乳腺癌细胞对长春碱类药物的耐药性有关提供了重要证据。本研究还表明，抗雌激素药物（如氟维司群）的联合应用可能是一种新的策略，可以逆转 ER 介导的化疗耐药性，或使 ER+乳腺癌肿瘤对长春碱类药物和其他可能的化疗药物敏感。
