Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death

PloS One
Brian J GirardJulie H Ostrander

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 (ERRγ) promoted cell survival in the presence of Tam. Overexpression of ERRγ in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERRγ 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 ERRγ reduced Tam-...Continue Reading

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Citations

Mar 22, 2016·Gene·Gangadhara Reddy Sareddy, Ratna K Vadlamudi
May 15, 2015·Journal of Experimental & Clinical Cancer Research : CR·Subha MadhavanRebecca B Riggins
Feb 3, 2016·Journal of Molecular Endocrinology·Katherine A LeehyJulie H Ostrander
Nov 24, 2018·Environmental Science and Pollution Research International·Bin HuangXuejun Pan
Jan 20, 2018·Molecular Cancer Research : MCR·Thu H TruongJulie H Ostrander

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Methods Mentioned

BETA
transgenic
biopsy
transfection
scraping
Assay
FACS
PCR
flow cytomety

Software Mentioned

ImageJ
FlowJo

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