Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Int J Oncol. 2010 Feb;36(2):451-8.
Endocrine therapies targeting estrogen action are pivotal for the prevention and treatment of ER-positive breast cancers. Previous studies sought to recreate hormone responsiveness by the stable expression of ERalpha in the ER-negative MDA-MB-231 breast cancer cells. Paradoxically, estrogen inhibits breast cancer cell growth when an exogenous ERalpha is expressed. In this study, we have built on previous studies by developing a Tet-off adenoviral system to express ERalpha in the ER-negative SKBr3 breast cancer cells that over-express both EGFR and HER2. This system efficiently delivers ERalpha and the expression level of ERalpha is controlled by doxycycline in a concentration-dependent manner. The growth of SKBr3 was inhibited by ERalpha expression and further inhibited in the presence of 1 nM 17beta-estradiol. SKBr3 cells were arrested at G0/G1 cell cycle upon ERalpha expression, which corresponded to an increase of p21Cip1/Waf1, hypo-phosphorylation of pRb and decrease of E2F1. Estrogen also reduced EGFR and HER2 expression in SKBr3 cells after ERalpha was expressed. Given that estrogen-induced increase of p21Cip1/Waf1 and decrease of E2F1 was also observed in MDA-MB-231 cells stably transfected with ERalpha, our results suggest that a common pathway might be shared by different breast cancer cell lines whose growth is suppressed by ectopic ERalpha and estrogen.
针对雌激素作用的内分泌治疗对于预防和治疗 ER 阳性乳腺癌至关重要。以前的研究试图通过在 ER 阴性 MDA-MB-231 乳腺癌细胞中稳定表达 ERalpha 来重现激素反应性。矛盾的是，当表达外源性 ERalpha 时，雌激素会抑制乳腺癌细胞的生长。在这项研究中，我们通过开发 Tet-off 腺病毒系统，在过度表达 EGFR 和 HER2 的 ER 阴性 SKBr3 乳腺癌细胞中表达 ERalpha，进一步研究了这一问题。该系统有效地递呈 ERalpha，其表达水平可通过浓度依赖性方式由强力霉素控制。ERalpha 的表达抑制了 SKBr3 的生长，而在 1 nM 17β-雌二醇存在下，其生长进一步受到抑制。SKBr3 细胞在 ERalpha 表达时被阻滞在 G0/G1 细胞周期，这与 p21Cip1/Waf1 的增加、pRb 的低磷酸化和 E2F1 的减少相对应。雌激素在 SKBr3 细胞中表达 ERalpha 后，也降低了 EGFR 和 HER2 的表达。鉴于在稳定转染 ERalpha 的 MDA-MB-231 细胞中也观察到雌激素诱导的 p21Cip1/Waf1 增加和 E2F1 减少，我们的结果表明，不同乳腺癌细胞系的生长可能受到外源性 ERalpha 和雌激素的抑制，它们可能共享一个共同的通路。
