Molecular Modulation of Estrogen-Induced Apoptosis in Long-Term Estrogen-Deprived Breast Cancer Cells
Sweeney, Elizabeth E.
Jordan, V. Craig
Estrogen receptor (ER)-positive breast cancer cell lines have been instrumental in modeling breast cancer and providing an opportunity to document the development and evolution of acquired anti-hormone resistance. Models of long-term estrogen-deprived breast cancer cells are utilized in the laboratory to mimic clinical aromatase inhibitor-resistant breast cancer and serve as a tool to discover new therapeutic strategies. The MCF-7:5C and MCF-7:2A subclones were generated through long-term estrogen deprivation of ER-positive MCF-7 cells, and represent anti-hormone resistant breast cancer. MCF-7:5C cells paradoxically undergo estrogen-induced apoptosis within seven days of estrogen (estradiol, E2) treatment; MCF-7:2A cells also experience E2-induced apoptosis but evade dramatic cell death until approximately 14 days of treatment. Our data suggest that MCF-7:2A cells employ stronger antioxidant defense mechanisms than do MCF-7:5C cells, and that oxidative stress is ultimately required for MCF-7:2A cells to die in response to E2 treatment. Tumor necrosis factor (TNF) family member activation also correlates with E2-induced apoptosis in MCF-7:2A cells; up-regulation of TNFα occurs simultaneously with oxidative stress activation. Additionally, increased insulin-like growth factor receptor beta (IGF-1Rβ) confers a mechanism of growth and anti-apoptotic advantage in MCF-7:2A cells.Hormone replacement therapy (HRT) is widely used to manage menopausal symptoms in women, and can comprise an estrogen alone or an estrogen combined with a progestin. The Women's Health Initiative demonstrated in their randomized trials that estrogen alone HRT decreases the risk of breast cancer in post-menopausal women, while combined estrogen plus a progestin (medroxyprogesterone acetate, MPA) HRT increases this risk. We sought to elucidate the mechanism through which these opposing effects occur. The data suggests that MPA acts as a glucocorticoid which blocks estrogen-induced apoptosis in long-term estrogen-deprived breast cancer cells thereby increasing cancer risk.
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Obiorah, Ifeyinwa Emmanuela (Georgetown University, 2014)Development of acquired antihormone resistance exposes a vulnerability in estrogen receptor (ER) positive breast cancer: estrogen induced apoptosis. Estrogen (E2) induces apoptosis in long-term E2-deprived MCF7 cells ...