Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Division of Molecular Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cancer Res. 2014 Oct 1;74(19):5469-79. doi: 10.1158/0008-5472.CAN-13-3429. Epub 2014 Aug 21.
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 α (ERα) transcriptional regulation of gene expression. Using ChIP-seq analysis, we demonstrate that RIP140 shares more than 80% of its binding sites with ERα, colocalizing with its interaction partners FOXA1, GATA3, p300, CBP, and p160 family members at H3K4me1-demarcated enhancer regions. RIP140 is required for ERα-complex formation, ERα-mediated gene expression, and ERα-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 ERα-mediated transcriptional regulation in breast cancer and response to tamoxifen treatment.
RIP140 是一种参与能量平衡、排卵和乳腺发育的转录共调节因子。尽管缺乏确凿的证据，但有报道表明 RIP140 与乳腺癌有关。在这里，我们探讨了 RIP140 在乳腺癌中的作用机制及其在雌激素受体 α（ERα）对基因表达的转录调控中的作用。通过 ChIP-seq 分析，我们证明 RIP140 与其结合位点有超过 80%的重叠，与其相互作用伙伴 FOXA1、GATA3、p300、CBP 和 p160 家族成员一起定位于 H3K4me1 标记的增强子区域。RIP140 是 ERα 复合物形成、ERα 介导的基因表达和 ERα 依赖性乳腺癌细胞增殖所必需的。沉默 RIP140 后受影响的基因可用于基于临床结果对接受他莫昔芬治疗的乳腺癌患者进行分层。重要的是，该基因特征仅在内分泌治疗条件下有效。总之，我们的数据表明，RIP140 在乳腺癌中 ERα 介导的转录调控和对他莫昔芬治疗的反应中发挥重要作用。
