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<p>Sex differences in the incidence and outcomes of non-reproductive cancers persist across many tumor types, even after adjustment for major exposure- and care-related factors. This review examines how sex-hormone signaling may contribute to these patterns through tumor-intrinsic mechanisms and regulation of the tumor microenvironment. In tumor cells, ER, AR and PR mediate classical nuclear transcriptional programs, whereas membrane-associated or cytoplasmic receptor pools, together with GPER, support rapid non-genomic signaling through PI3K/AKT, MAPK/ERK and related kinase or second-messenger pathways. Intratumoral steroid handling can create local ligand conditions that differ from circulating hormone levels and modify context-specific receptor activity. Hormonal context may also influence vascular, stromal and immune phenotypes. Clinically, sex-hormone-related tumor states may be better captured by integrated activity-based readouts, including receptor status, pathway activation, local steroid availability and immune context, rather than receptor immunostaining alone. Overall, sex-hormone signaling offers a hypothesis-generating framework for understanding sex-biased tumor biology beyond traditional hormone-driven cancers, but its clinical relevance requires further mechanistic and prospective validation.</p>

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Sex differences in non-reproductive cancers: mechanistic roles of sex-hormone signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Jingsheng Xu,
  • Xinyu Zhang,
  • Zhenyu Li,
  • Siqi Li,
  • Anhui Ning,
  • Dingding Li,
  • Minjie Chu,
  • Haiyan Gong

摘要

Sex differences in the incidence and outcomes of non-reproductive cancers persist across many tumor types, even after adjustment for major exposure- and care-related factors. This review examines how sex-hormone signaling may contribute to these patterns through tumor-intrinsic mechanisms and regulation of the tumor microenvironment. In tumor cells, ER, AR and PR mediate classical nuclear transcriptional programs, whereas membrane-associated or cytoplasmic receptor pools, together with GPER, support rapid non-genomic signaling through PI3K/AKT, MAPK/ERK and related kinase or second-messenger pathways. Intratumoral steroid handling can create local ligand conditions that differ from circulating hormone levels and modify context-specific receptor activity. Hormonal context may also influence vascular, stromal and immune phenotypes. Clinically, sex-hormone-related tumor states may be better captured by integrated activity-based readouts, including receptor status, pathway activation, local steroid availability and immune context, rather than receptor immunostaining alone. Overall, sex-hormone signaling offers a hypothesis-generating framework for understanding sex-biased tumor biology beyond traditional hormone-driven cancers, but its clinical relevance requires further mechanistic and prospective validation.