Endocrine disruption of early uterine differentiation causes adenocarcinoma mediated by Wnt/β-catenin- and PI3K/AKT signaling

Abstract

Developmental exposure to non-mutagenic environmental factors can contribute to cancer risk, but the underlying mechanisms are not understood. We used a mouse model of endometrial adenocarcinoma that results from brief developmental exposure to an estrogenic chemical, diethylstilbestrol (DES), to determine causative factors. Single cell RNA sequencing and spatial transcriptomics of adult uteri revealed new markers of uterine epithelial stem cells, identified luminal and glandular progenitor cells, and defined a glandular epithelial differentiation trajectory. Neonatal DES exposure disrupted uterine epithelial differentiation, resulting in widespread activation of Wnt signaling and a failure to generate epithelial stem cells or distinguishable glandular and luminal epithelial cells. The endometrial stromal cells activated inflammatory signals and oxidative stress. Together, these changes activated PI3K/AKT signaling to drive malignant transformation. These findings explain how human cancers, which are often associated with abnormal activation of PI3K/AKT signaling, could result from exposure to environmental insults during development.

Environmental Exposure to Persistent Organic Pollutants and Its Association with Endometriosis Risk: Implications in the Epithelial–Mesenchymal Transition Process

“…Human hepatocyte cultures exposed to some OCPs also increased the expression of the DKK1 gene [85]. It has also been recently reported that in vivo models of endometrial cancer exposed to other endocrine-disrupting chemicals such as diethylstilbestrol (DES) aberrantly activated the WNT/β-catenin and TGFβ/PDGFRα-related PI3K/AKT signaling pathways [86].…”