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Evolutionary perspectives on endometrial cancer: antagonistic pleiotropy
1Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.
Molecular & Cellular Oncology
|June 19, 2026
Summary
Endometrial cancer is rising due to modern lifestyles. Evolutionary mismatch explains how pathways vital for reproduction become harmful, promoting cancer development.
Area of Science:
- Evolutionary medicine
- Reproductive biology
- Molecular oncology
Background:
- Rising incidence of endometrial cancer, particularly early-onset cases.
- Modern environmental and lifestyle factors (obesity, insulin resistance) linked to increased risk.
- TCGA classification reveals molecular heterogeneity (DNA repair defects, PI3K-AKT-mTOR, p53 pathway alterations).
Purpose of the Study:
- Reinterpret endometrial cancer pathogenesis using evolutionary mismatch and antagonistic pleiotropy.
- Examine dual roles of key signaling pathways across the lifespan.
- Provide a coherent framework for understanding endometrial cancer development.
Main Methods:
- Integrate evidence from molecular oncology, reproductive biology, and evolutionary medicine.
- Analyze the roles of PI3K-AKT-mTOR and p53 pathways in reproduction and tumorigenesis.
- Examine pathway interactions and their contribution to oncogenic phenotypes.
Main Results:
- PI3K-AKT-mTOR pathway essential for reproduction but overactivated by modern overnutrition, promoting hyperplasia.
- p53 pathway supports genome integrity and placental function but dysregulation contributes to senescence and tumor progression.
- Interactions between pathways amplify oncogenic phenotypes like TP53 mutations and PI3K hyperactivation.
Conclusions:
- Molecular alterations in endometrial cancer are maladaptive consequences of evolutionary pressures in modern environments.
- An evolutionary medicine perspective offers a unified understanding of endometrial cancer pathogenesis.
- Understanding these evolutionary underpinnings may inform future prevention and treatment strategies.
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