Deficiency in homologous recombination repair (HRR) is frequently associated with hormone-responsive cancers, especially the epithelial ovarian cancer (EOC) which shows 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. Methods: We analyzed the estrogen receptor α (ERα) binding profile in EOC cell lines and investigated its association with genome instability, HRR deficiency and sensitivity to chemotherapy using extensive public datasets and in vitro/in vivo experiments. Results: We found an inverse correlation between estrogen signaling and HRR activity in EOC, and the genome-wide collaboration between ERα and the co-repressor CtBP. Though the non-classical AP-1-mediated ERα signaling, their targets were highly enriched by HRR genes. We found that depleting ERα in EOC cells up-regulates HRR activity and HRR gene expression. Consequently, 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 ESR1 expression are associated with chemo-sensitivity and the favorable survival of EOC patients. Conclusion: These findings characterize a novel role of ERα in mediating the molecular connection between hormone and HRR in EOC and encourage hormone replacement therapy for EOC patients.

中文翻译：

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卵巢癌中的非经典雌激素信号改善了化疗敏感性和患者预后。

同源重组修复 (HRR) 缺陷通常与激素反应性癌症相关，尤其是上皮性卵巢癌 (EOC)，其在多达一半的病例中显示出 HRR 缺陷。然而，雌激素信号与 EOC 中 HRR 缺乏之间是否存在分子联系尚不清楚。方法：我们分析了 EOC 细胞系中的雌激素受体 α (ERα) 结合谱，并使用广泛的公共数据集和体外/体内实验研究了其与基因组不稳定性、HRR 缺陷和化疗敏感性的关联。结果：我们发现 EOC 中雌激素信号传导和 HRR 活性之间存在负相关，以及 ERα 和共同抑制因子 CtBP 之间的全基因组协作。尽管非经典的 AP-1 介导的 ERα 信号传导，但其靶标被 HRR 基因高度富集。我们发现在 EOC 细胞中消耗 ERα 上调 HRR 活性和 HRR 基因表达。因此，雌激素信号增强了卵巢癌细胞对体外和体内化疗药物的敏感性。大规模分析进一步表明，雌激素替代和 ESR1 表达与 EOC 患者的化疗敏感性和良好的生存相关。结论：这些发现表征了 ERα 在介导 EOC 中激素和 HRR 之间的分子联系中的新作用，并鼓励对 EOC 患者进行激素替代治疗。大规模分析进一步表明，雌激素替代和 ESR1 表达与 EOC 患者的化疗敏感性和良好的生存相关。结论：这些发现表征了 ERα 在介导 EOC 中激素和 HRR 之间的分子联系中的新作用，并鼓励对 EOC 患者进行激素替代治疗。大规模分析进一步表明，雌激素替代和 ESR1 表达与 EOC 患者的化疗敏感性和良好的生存相关。结论：这些发现表征了 ERα 在介导 EOC 中激素和 HRR 之间的分子联系中的新作用，并鼓励对 EOC 患者进行激素替代治疗。