High-grade serous ovarian cancer (HGSOC) represents the most lethal subtype of ovarian cancer, largely due to being commonly diagnosed at advanced stages. The early molecular mechanisms underlying ovarian carcinogenesis remain poorly defined, posing challenges to the development of prevention and early detection strategies. Here we dissect the molecular mechanisms of sex steroid hormone signaling throughout the decades-long evolution of HGSOC precursor lesions, which predominantly originate from secretory epithelial cells of fallopian tubes (FT). We also discuss the prognostic significance of sex steroid receptor isoforms and steroid metabolizing enzymes in HGSOCs. Finally, we provide a comprehensive gene expression atlases of sex steroid receptors, steroidogenic, and steroid-metabolizing enzymes across different cell populations in pre- and postmenopausal FTs, and HGSOCs, using published single-cell RNA sequencing datasets. These atlases reveal that secretory epithelial cells and stromal populations in FTs express sex steroid receptors and enzymes responsible for the formation and inactivation of genotoxic estrogen metabolites. In HGSOC, epithelial cells express various HSD17B isoforms and steroid conjugating enzymes, suggesting an enhanced ability to finely regulate the levels of bioactive sex steroids.

中文翻译：

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从输卵管上皮到高级别浆液性卵巢癌：性类固醇激素信号转导的单细胞分辨率综述


高级别浆液性卵巢癌 （HGSOC） 是卵巢癌中最致命的亚型，主要是由于通常在晚期被诊断出来。卵巢癌发生的早期分子机制仍然不明确，对预防和早期检测策略的开发构成挑战。在这里，我们剖析了 HGSOC 前体病变长达数十年演变过程中性类固醇激素信号传导的分子机制，这些病变主要起源于输卵管 （FT） 的分泌上皮细胞。我们还讨论了 HGSOCs 中性类固醇受体亚型和类固醇代谢酶的预后意义。最后，我们使用已发表的单细胞 RNA 测序数据集，提供了绝经前和绝经后 FT 和 HGSOC 中不同细胞群的性类固醇受体、类固醇生成和类固醇代谢酶的综合基因表达图谱。这些图谱显示，FT 中的分泌型上皮细胞和基质群表达负责遗传毒性雌激素代谢物形成和失活的性类固醇受体和酶。在 HGSOC 中，上皮细胞表达各种 HSD17B 亚型和类固醇结合酶，表明精细调节生物活性性类固醇水平的能力增强。