Abstract
Estrogen-related receptor alpha (ERRα) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRα is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRα expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRα and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRα and S6K1. We found that ERRα negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRα expression sensitized ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERRα and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation.
Highlights
Estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor and an important component of signaling networks in breast cancer cells.[1]
We identified high ERRα expression as a biomarker of response to tamoxifen in triple-negative breast cancers (TNBC),[18] a finding that may provide clinical benefit to this population of patients
Because ERRα can bind the same promoters as ERα, and because we found an association between high ERRα expression and a worse prognosis in breast cancer patients in our recent study,[18] we sought to investigate whether
Summary
Estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor and an important component of signaling networks in breast cancer cells.[1]. Because ERRα can bind the same promoters as ERα, and because we found an association between high ERRα expression and a worse prognosis in breast cancer patients in our recent study,[18] we sought to investigate whether. We investigated the correlation between ERRα expression and sensitivity to mTOR and S6K1 inhibition in breast cancer cell lines and mouse models. Neutral red assay to measure living cells was performed 2 or 5 days post treatment as previously described.[32,33]. Stable ERRα knockdown and control MDA-MB-231 luciferase-expressing cells were a generous gift from Donald P McDonnell (Duke University, Durham, NC, USA). The day, the media was replaced with DMEM containing 1% FBS and indicated cells were treated with 20 nM rapamycin. The following day, fresh media was added and cells were treated with rapamycin as indicated. Statistical significance was determined by paired Student’s t-test using Microsoft Excel
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