Complex Formation and Function of Estrogen Receptor α in Transcription Requires RIP140

Abstract

RIP140 is a transcriptional coregulator involved in energy homeostasis, ovulation, and mammary gland development. Although conclusive evidence is lacking, reports have implicated a role for RIP140 in breast cancer. Here, we explored the mechanistic role of RIP140 in breast cancer and its involvement in estrogen receptor a (ERa) transcriptional regulation of gene expression. Using ChIP-seq analysis, we demonstrate that RIP140 shares more than 80% of its binding sites with ERa, colocalizing with its interaction partners FOXA1, GATA3, p300, CBP, and p160 family members at H3K4me1-demarcated enhancer regions. RIP140 is required for ERa-complex formation, ERa-mediated gene expression, and ERa-dependent breast cancer cell proliferation. Genes affected following RIP140 silencing could be used to stratify tamoxifen-treated breast cancer cohorts, based on clinical outcome. Importantly, this gene signature was only effective in endocrine-treated conditions. Cumulatively, our data suggest that RIP140 plays an important role in ERa-mediated transcriptional regulation in breast cancer and response to tamoxifen treatment. Cancer Res; 74(19); 5469-79. Ó2014 AACR.

Involvement of receptor-interacting protein 140 in estrogen-mediated osteoclasts differentiation, apoptosis, and bone resorption

“…The expression of RIP140 could be regulated by estrogen in many cells, such as breast cancer cells, ovarian cancer cells, and kidney cells [23,25,28]. This was the first report that estrogen might regulate RIP140 expression in osteoclasts.…”

“…Recently, studies have shown that RIP140 was a critical player in estrogen-related disease. Rosell et al found that RIP140 was implicated in ERa-mediated transcriptional regulation in breast cancer and response to tamoxifen treatment [25]. Liu et al showed that RIP140 was involved in the fat and lipid metabolic regulation of estrogen [16].…”

Isoflavones in soy flour diet have different effects on whole‐genome expression patterns than purified isoflavone mix in human MCF‐7 breast tumors in ovariectomized athymic nude mice

“…RIP140 is required for normal mammary gland development, estrogen‐dependent transcription regulation, cell proliferation in breast cancer, and functions as a co‐activator for ERα‐responsive genes. High RIP40 expression was linked to poor survival of breast cancer patients . IL17BR was significantly increased by E 2 in the MCF‐7 cell line.…”

The first decade of estrogen receptor cistromics in breast cancer

“…This link between SRC3 gene targets and tamoxifen treatment is in line with previous reports describing increased SRC3 expression, in combination with increased ERBB2 expression, to correlate with a poor tamoxifen response (Osborne & Schiff 2003, Shou et al 2004, Hurtado et al 2008, Zhao et al 2009). Another ERα-interacting protein that can affect ERα complex formation and gene expression is the transcriptional regulator RIP140 (Rosell et al 2014). Genes under the specific control of RIP140 (identified by siRNA experiments) could be used to classify tamoxifen-treated patients on clinical outcome (Rosell et al 2014).…”

“…Another ERα-interacting protein that can affect ERα complex formation and gene expression is the transcriptional regulator RIP140 (Rosell et al 2014). Genes under the specific control of RIP140 (identified by siRNA experiments) could be used to classify tamoxifen-treated patients on clinical outcome (Rosell et al 2014). Both RIP140 and the p160 family members further stipulate the observation that the composition of the transcriptional complex may differ on a genome-wide scale, which could have direct physiological consequences on the level of transcriptional output and clinical response (Fig.…”