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 ERα in the ER-negative MDA-MB-231 breast cancer cells. Paradoxically, estrogen inhibits breast cancer cell growth when an exogenous ERα is expressed. In this study, we have built on previous studies by developing a Tet-off adenoviral system to express ERα in the ER-negative SKBr3 breast cancer cells that over-express both EGFR and HER2. This system efficiently delivers ERα and the expression level of ERα is controlled by doxycycline in a concentration-dependent manner. The growth of SKBr3 was inhibited by ERα expression and further inhibited in the presence of 1 nM 17β-estradiol. SKBr3 cells were arrested at G0/G1 cell cycle upon ERα 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 ERα 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 ERα, our results suggest that a common pathway might be shared by different breast cancer cell lines whose growth is suppressed by ectopic ERα and estrogen.

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