PLOS Biology · 13 authors, 6 centres
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This preclinical mouse study used single-cell sequencing to show that brief neonatal exposure to the estrogenic chemical diethylstilbestrol (DES) disrupts normal uterine epithelial cell differentiation, leading to the activation of Wnt/β-catenin and PI3K/AKT signaling pathways and the development of endometrial adenocarcinoma in adulthood.
In control mice, they identified a distinct uterine epithelial stem cell population that differentiates into separate luminal and glandular progenitor cells. Instead, a single abnormal progenitor cell population with widespread Wnt/β-catenin activation was observed. The study found that this altered epithelial differentiation, combined with stromal inflammation and oxidative stress, activated PI3K/AKT signaling, leading to malignant transformation marked by phospho-AKT and OLFM4 protein. The findings propose a mechanistic pathway from developmental exposure to an endocrine disruptor to adult-onset cancer, suggesting a potential role for environmental insults in some human cancers.
