Evolutionary perspectives on endometrial cancer: antagonistic pleiotropy.

Abstract

The incidence of endometrial cancer is increasing worldwide, with a particularly marked rise in early-onset cases. Modern environmental and lifestyle factors, including low parity, delayed childbirth, obesity, insulin resistance, and chronic inflammation, are thought to contribute to this trend. Although TCGA-based molecular classification has revealed substantial heterogeneity-such as defects in DNA repair, constitutive activation of the PI3K-AKT-mTOR pathway, and disruption of the p53 pathway-the reasons these abnormalities preferentially accumulate in endometrial cancer remain incompletely understood. In this review, we reinterpret the molecular pathogenesis of endometrial cancer through the frameworks of evolutionary mismatch and antagonistic pleiotropy, conceptualizing the disease as a continuum linking reproduction, aging, and tumorigenesis. We integrate evidence from molecular oncology, reproductive biology, and evolutionary medicine to examine how key signaling pathways acquire dual roles across the lifespan. The PI3K-AKT-mTOR pathway is indispensable for reproductive function and endometrial regeneration, yet becomes chronically overactivated under contemporary conditions of overnutrition and obesity, thereby promoting hyperplasia and tumorigenesis. Similarly, the p53 pathway supports genome integrity and placental function during reproduction, but age- and inflammation-associated dysregulation induces cellular senescence and facilitates tumor progression. Importantly, these pathways interact and reinforce each other, amplifying oncogenic phenotypes such as TP53 mutations and PI3K hyperactivation. Collectively, the molecular alterations observed in endometrial cancer can be understood as maladaptive consequences of reproductive systems shaped by evolution but exposed to modern environments. Therefore, an evolutionary medicine perspective may provide a coherent framework for understanding the development of endometrial cancer.