PAX2-null progenitors define multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium

The oviducts contain high grade serous cancer precursors, which are -H2AXp and p53 mutation positive. Secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer. We evaluated PAX2 expression in proliferating oviductal cells, normal mucosa, SCOUTs, Walthard cell nests, STINs and HGSCs. Non-ciliated cells in normal mucosa were PAX2 positive but became PAX2 negative in multilayered epithelium. PAX2 negative SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a tubal phenotype and were ALDH1 negative. Type II displayed a columnar to pseudostratified phenotype, with an EZH2,ALDH1, -catenin, Stathmin, LEF1, RCN1 and RUNX2 expression signature . This study, for the first time, links PAX2 negative with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2) calcium binding (RCN1) and oncogenesis (Stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target of early prevention.

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Ning G, Bijron JG, Yamamoto Y, Wang X, Howitt BE, Herfs M, Yang E, Hong Y, Cornille M, Wu L, Hanamornroongruang S, McKeon FD, Crum CP, Xian W