雌激素受体α在介导乳腺癌细胞化疗耐药中的作用。
The role of estrogen receptor alpha in mediating chemoresistance in breast cancer cells.
机构信息
Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China.
出版信息
J Exp Clin Cancer Res. 2012 May 3;31(1):42. doi: 10.1186/1756-9966-31-42.
INTRODUCTION
Previous studies suggested that estrogen receptor alpha (ERα) plays an important role in the chemoresistance of breast cancers. However, large random trials failed to demonstrate any benefit of the concurrent estrogen antagonist tamoxifen on the chemotherapy efficacy. Thus, in the present study, the importance of the role of ERα in the chemoresistance of breast cancer cells was investigated.
METHODS
The ERα-transfected Bcap37 cells and natural ERα-positive T47D breast cancer cells were treated using chemotherapeutic agents with or without 17-beta estradiol (E2) pretreatment. Their viabilities were assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. The dead cell rates were determined using propidium iodide dye exclusion tests, and the expression levels of Bcl-2 and Bax were detected through Western blot analysis. The effects of E2 on the growth of breast cancer cells were also determined via cell growth curve and cell cycle analysis.
RESULTS
ERα activation by E2 increased the sensitivity of natural ERα-positive T47D breast cancer cells to chemotherapeutic agents. However, the increase in ERα expression in ERα-negative Bcap37 breast cancer cells also significantly increased their resistance. These phenomena cannot be explained by asserting that ERα mediated the chemoresistance of breast cancer cells by regulating the expression of Bcl-2 and Bax. Our findings show that ERα activation upregulated the expression of Bcl-2 in natural ERα-positive T47D breast cancer cells, whereas ERα activation by E2 downregulated and upregulated the Bcl-2 and Bax expression levels, respectively, in ERα-transfected Bcap37 cells. This phenomenon was due to the influence of ERα on the growth of breast cancer cells. Specifically, ERα activation enhanced the growth of natural ERα-positive breast cancer cells and thus increased their sensitivity to chemotherapeutic agents. However, ERα activation also inhibited the growth of ERα-transfected Bcap37 cells and increased the resistance of cancer cells to chemotherapeutic agents. Chemoresistance of ERα-transfected Bcap37 cells was only due to the specific growth inhibition by E2, which is not applicable to common ERα-positive breast cancer cells.
CONCLUSIONS
Although ERα was associated with chemoresistance of breast cancers, ERα itself did not mediate this resistance process.
简介
先前的研究表明，雌激素受体 α（ERα）在乳腺癌的化疗耐药中发挥着重要作用。然而，大型随机试验未能证明同时使用雌激素拮抗剂他莫昔芬对化疗疗效有任何益处。因此，在本研究中，我们研究了 ERα 在乳腺癌细胞化疗耐药中的重要作用。
方法
用化疗药物处理转染 ERα 的 Bcap37 细胞和天然 ERα 阳性 T47D 乳腺癌细胞，并在预处理时加入 17-β 雌二醇（E2）。用 3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐测定法评估细胞活力。用碘化丙啶染料排除试验测定死细胞率，并通过 Western blot 分析检测 Bcl-2 和 Bax 的表达水平。还通过细胞生长曲线和细胞周期分析测定 E2 对乳腺癌细胞生长的影响。
结果
E2 激活 ERα 增加了天然 ERα 阳性 T47D 乳腺癌细胞对化疗药物的敏感性。然而，ERα 阴性 Bcap37 乳腺癌细胞中 ERα 表达的增加也显著增加了其耐药性。这些现象不能用 ERα 通过调节 Bcl-2 和 Bax 的表达来介导乳腺癌细胞化疗耐药的说法来解释。我们的研究结果表明，ERα 激活上调了天然 ERα 阳性 T47D 乳腺癌细胞中 Bcl-2 的表达，而 E2 激活 ERα 下调并上调了转染 ERα 的 Bcap37 细胞中 Bcl-2 和 Bax 的表达水平。这种现象是由于 ERα 对乳腺癌细胞生长的影响所致。具体而言，ERα 激活增强了天然 ERα 阳性乳腺癌细胞的生长，从而增加了它们对化疗药物的敏感性。然而，ERα 激活也抑制了转染 ERα 的 Bcap37 细胞的生长，并增加了癌细胞对化疗药物的耐药性。转染 ERα 的 Bcap37 细胞的化疗耐药仅归因于 E2 的特定生长抑制作用，而不适用于常见的 ERα 阳性乳腺癌细胞。
结论
尽管 ERα 与乳腺癌的化疗耐药有关，但 ERα 本身并未介导这种耐药过程。
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