Molecular Modulation of Estrogen-Induced Apoptosis in Long-Term Estrogen-Deprived Breast Cancer Cells
Sweeney, Elizabeth E.
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.
Embargo Lift Date
Showing items related by title, author, creator and subject.
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 ...
Short- and long-term impact of receiving genetic mutation results in women at increased risk for hereditary breast cancer Lim, Jacqueline; Macluran, Mariette; Price, Melanie; Bennett, Barbara; Butow, Phyllis (2004-04)