The Modulation of Estrogen Induced Apoptosis in Breast Cancer
Obiorah, Ifeyinwa Emmanuela
Jordan, Virgil C
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 (MCF7:5C). Triphenylethylenes (TPEs) which are structurally similar to 4-hydroxytamoxifen (4OHT) were used for mechanistic studies of estrogen induced apoptosis. These TPEs all stimulate growth in MCF-7 cells but unlike the planar estrogens they block estrogen induced apoptosis in the long term estrogen deprived MCF7:5C cells. The TPE:ER complexes did not readily recruit the coactivator SRC3 or ER to the PS2 promoter in MCF-7 and MCF7:5C cells and molecular modeling showed that they prefer to bind to the ER in an antagonistic fashion i.e.: helix 12 not sealing the ligand binding domain (LBD) effectively and therefore reduces critical SRC3 binding. The fully activated ER complex with helix 12 sealing the LBD is suggested to be the appropriate trigger to initiate rapid estrogen induced apoptosis. We determined that E2- induced apoptosis is a delayed process, while paclitaxel immediately causes a G2/M blockade and induces death of MCF7:5C cells. We are first to show that the cellular commitment for E2-triggered apoptosis occur after 24 h. A sequential activation of the intrinsic pathway occurs at 36h of E2 treatment with subsequent induction of the extrinsic apoptotic pathway by 48h. Unlike the trigger by E2 that occurs after 24h the trigger of apoptosis for BP occurs at 4 days with quantifiable apoptotic changes noted at 6 days. A prolonged induction of endoplasmic reticulum stress(ERS) and inflammatory stress (IS) response genes was observed with subsequent activation of apoptosis related genes in the second week of treatment with BP. Phytoestrogens which are planar compounds act like steroidal estrogens and induce apoptosis in MCF7:5C cells through the ERα and induces ERS, IS and apoptosis related genes as the steroidal estrogens. These data indicate that estrogen-induced apoptosis involves a novel, multidynamic process that is distinctly different from that of a classic cytotoxic chemotherapeutic drug used in breast cancer.
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Molecular Modulation of Estrogen-Induced Apoptosis in Long-Term Estrogen-Deprived Breast Cancer Cells Sweeney, Elizabeth E. (Georgetown University, 2014)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 ...