title: Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology.
abstract: Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n=8) and ugeARKO (n=7) uteri. Uterine weight was significantly (P=0.002) increased in ugePTENARKO (374±97 mg (mean±s.e.)) compared with WT (97±6 mg), ugeARKO (94±12 mg), and ugePTENKO (205±33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.
authors.affiliation: ANZAC Research InstituteUniversity of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jaesung Peter
authors.initials: JP
authors.lastname: Choi
authors.affiliation: ANZAC Research InstituteUniversity of Sydney, Sydney, New South Wales, Australia.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: ANZAC Research InstituteUniversity of Sydney, Sydney, New South Wales, Australia djh@anzac.edu.au.
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.affiliation: ANZAC Research InstituteUniversity of Sydney, Sydney, New South Wales, Australia.
authors.forename: Ulla
authors.initials: U
authors.lastname: Simanainen
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D018345:Mice, Knockout; D009929:Organ Size; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D014599:Uterus / Q000378:metabolism / Q000473:pathology*
chemical_list: C000607144:AR protein, mouse; D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: PTEN; androgen; androgen receptor; mouse model; uterine disorder