Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death.
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ABSTRACT: Tamoxifen (Tam) is the only FDA-approved chemoprevention agent for pre-menopausal women at high risk for developing breast cancer. While Tam reduces a woman's risk of developing estrogen receptor positive (ER+) breast cancer, the molecular mechanisms associated with risk reduction are poorly understood. Prior studies have shown that cytoplasmic proline, glutamic acid and leucine rich protein 1 (PELP1) promotes Tam resistance in breast cancer cell lines. Herein, we tested for PELP1 localization in breast epithelial cells from women at high risk for developing breast cancer and found that PELP1 was localized to the cytoplasm in 36% of samples. In vitro, immortalized HMECs expressing a nuclear localization signal (NLS) mutant of PELP1 (PELP1-cyto) were resistant to Tam-induced death. Furthermore, PELP1-cyto signaling through estrogen-related receptor gamma (ERR?) promoted cell survival in the presence of Tam. Overexpression of ERR? in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERR? sensitized PELP1-cyto expressing HMECs to Tam. Moreover, Tam-induced HMEC cell death was independent of apoptosis and involved accumulation of the autophagy marker LC3-II. Expression of PELP1-cyto and ERR? reduced Tam-induced LC3-II accumulation, and knockdown of ERR? increased LC3-II levels in response to Tam. Additionally, PELP1-cyto expression led to the upregulation of MMP-3 and MAOB, known PELP1 and ERR? target genes, respectively. Our data indicate that cytoplasmic PELP1 induces signaling pathways that converge on ERR? to promote cell survival in the presence of Tam. These data suggest that PELP1 localization and/or ERR? activation could be developed as tissue biomarkers for Tam responsiveness.
SUBMITTER: Girard BJ
PROVIDER: S-EPMC4366195 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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