title: Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion.
abstract: Estrogen receptor alpha (ERα) 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 ERα influences proliferation in breast cancer cells. Our results show that ERα protein is cell cycle-regulated in human breast cancer cells and that the presence of 17-β-estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5 hours, P < 0.05) compared with unliganded conditions. The alterations in cell cycle duration were observed in the S and G2/M phases, whereas the G1 phase was indistinguishable under liganded and unliganded conditions. In addition, ERα knockdown in MCF-7 cells accelerated mitotic exit, whereas transfection of ERα-negative MDA-MB-231 cells with exogenous ERα significantly shortened the S and G2/M phases (by 9.1 hours, 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 G2/M phases than fulvestrant does, presumably because of the destabilizing effect of fulvestrant on ERα protein. Together, these results show that ERα modulates breast cancer cell proliferation by regulating events during the S and G2/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 ERα, such as tamoxifen.
authors.affiliation: a Department of Experimental Radiation Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: JavanMoghadam
authors.affiliation: b Department of Biology and Biochemistry , University of Houston , Houston , TX , USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Weihua
authors.affiliation: c Department of Breast Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.affiliation: a Department of Experimental Radiation Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
mesh_terms: D016590:Aphidicolin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008148:Lovastatin / Q000494:pharmacology; D061986:MCF-7 Cells; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D008024:Ligands; D034741:RNA, Small Interfering; D013629:Tamoxifen; D000077267:Fulvestrant; D016590:Aphidicolin; D004958:Estradiol; D008148:Lovastatin
keywords: Estrogen receptor alpha; breast neoplasms; cell cycle; estradiol; receptor modulators; selective estrogen