title: PTEN loss and HOXA10 expression are associated with ovarian endometrioid adenocarcinoma differentiation and progression.
abstract: Epithelial ovarian cancer is a heterogeneous disease that is subdivided into five major histotypes but the mechanisms driving their differentiation are not clear. Mutations in adenomatous polyposis coli (APC) and β-catenin are commonly observed in the human ovarian endometrioid adenocarcinoma (OEA) patients. However, the mechanisms subsequent to APC deletion in ovarian tumorigenesis have not been well characterized. We have conditionally deleted APC in the murine ovarian surface epithelium (OSE) and showed that its loss leads to development of epithelial inclusion cysts. High-grade OEAs with tightly packed villoglandular histology were observed in older APC-deleted mice. Phosphatase and tensin homolog (PTEN) expression was elevated in the early lesions but lost after progression to the more advanced tumors. Knockdown of APC or expression of a gain-of-function β-catenin similarly induced human OSE cells to develop tumors with endometrioid histology in xenografts. Expression of HOXA10 was induced in both the advanced APC-deleted murine tumors and in the tumor xenografts of human OSE cells with knocked-down APC. These results show that reduced APC activity is sufficient to induce formation of epithelial inclusion cysts and support OEA development and suggest that induced HOXA10 expression and loss of PTEN are key mechanisms driving endometrioid histotype differentiation and progression.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Tanwar
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kaneko-Tarui
authors.forename: Ho-Joon
authors.initials: HJ
authors.lastname: Lee
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhang
authors.forename: Jose M
authors.initials: JM
authors.lastname: Teixeira
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000077216:Carcinoma, Ovarian Epithelial; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D005260:Female; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010053:Ovary / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D051176:beta Catenin; C092119:Hoxa10 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse