Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion

Estrogen receptor alpha (ER) has been implicated in several cell cycle regulatory events and is an important predictive marker of disease outcome in breast cancer patients. Here, we aimed to elucidate the mechanism through which ER influences proliferation in breast cancer cells. Our results show that ER protein is cell cycle-regulated in human breast cancer cells and that the presence of 17--estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5hours, P < 0.05) compared with unliganded conditions. The alterations in cell cycle duration were observed in the S and G(2)/M phases, whereas the G(1) phase was indistinguishable under liganded and unliganded conditions. In addition, ER knockdown in MCF-7 cells accelerated mitotic exit, whereas transfection of ER-negative MDA-MB-231 cells with exogenous ER significantly shortened the S and G(2)/M phases (by 9.1hours, P < 0.05) compared with parental cells. Finally, treatment of MCF-7 cells with antiestrogens revealed that tamoxifen yields a slower cell cycle progression through the S and G(2)/M phases than fulvestrant does, presumably because of the destabilizing effect of fulvestrant on ER protein. Together, these results show that ER modulates breast cancer cell proliferation by regulating events during the S and G(2)/M phases of the cell cycle in a ligand-dependent fashion. These results provide the rationale for an effective treatment strategy that includes a cell cycle inhibitor in combination with a drug that lowers estrogen levels, such as an aromatase inhibitor, and an antiestrogen that does not result in the degradation of ER, such as tamoxifen.