ERα-CtBP-mediated repression of Homologous-recombination repair in ovarian cancer improves chemo-sensitivity [ChIP-seq]

Deficiency in homologous recombination repair (HRR) is frequently associated with hormone-responsive cancers. Epithelial ovarian cancer (EOC) is a typical hormone-related tumor, with defects of HRR in up to half of cases. However, whether there are molecular connections between estrogen signaling and HRR deficiency in EOC remains unknown. Here we report an inverse correlation between estrogen signaling and HRR activity in EOC. Genome-wide mapping of ERα reveals ERα co-bindings with co-repressor CtBP, especially on many HRR gene loci, in EOC cells but not in breast cancer cells. Consistently, depleting ERα in EOC cells up-regulates HRR activity and HRR gene expression. Importantly, estrogen signaling enhances the sensitivity of ovarian cancer cells to chemotherapy agents in vitro and in vivo. Large-scale analyses further indicate that estrogen replacement and ERα expression are associated with favorable survival of EOC patients. These findings characterize a novel role of ERα in mediating the molecular connection between hormone and HRR in EOC, and suggest that estrogen signaling may improve the treatment outcome of EOC patients.

同源重组修复（homologous recombination repair, HRR）缺陷常与激素响应性癌症相关。上皮性卵巢癌（epithelial ovarian cancer, EOC）是典型的激素相关肿瘤，约半数病例存在HRR缺陷。然而，上皮性卵巢癌中雌激素信号通路（estrogen signaling）与HRR缺陷之间是否存在分子关联仍不明确。本研究报道了上皮性卵巢癌中雌激素信号通路与HRR活性呈负相关。对雌激素受体α（estrogen receptor α, ERα）的全基因组定位分析显示，在上皮性卵巢癌细胞中，ERα可与共抑制因子CtBP（co-repressor CtBP）发生共结合，尤其富集于诸多HRR基因位点，而乳腺癌细胞中则无此现象。与之相符的是，在上皮性卵巢癌细胞中敲低ERα可上调HRR活性及HRR基因的表达水平。重要的是，雌激素信号通路在体外及体内均可增强卵巢癌细胞对化疗药物的敏感性。大规模分析进一步表明，雌激素替代疗法（estrogen replacement）与ERα表达均与上皮性卵巢癌患者的良好生存预后相关。本研究阐明了ERα在上皮性卵巢癌中介导激素信号与HRR之间分子关联的新功能，并提示雌激素信号通路或可改善上皮性卵巢癌患者的治疗结局。