title: Follicle Depletion Provides a Permissive Environment for Ovarian Carcinogenesis.
abstract: We modeled the etiology of postmenopausal biology on ovarian cancer risk using germ cell-deficient white-spotting variant (Wv) mice, incorporating oncogenic mutations. Ovarian cancer incidence is highest in peri- and postmenopausal women, and epidemiological studies have established the impact of reproductive factors on ovarian cancer risk. Menopause as a result of ovarian follicle depletion is thought to contribute to higher cancer risk. As a consequence of follicle depletion, female Wv mice develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis frequently found in postmenopausal human ovaries. Lineage tracing using MISR2-Cre indicated that the tubular adenomas that developed in Wv mice were largely derived from the MISR2 lineage, which marked only a fraction of ovarian surface and oviduct epithelial cells in wild-type tissues. Deletion of p27, either heterozygous or homozygous, was able to convert the benign tubular adenomas into more proliferative tumors. Restricted deletion of p53 in Wv/Wv mice by either intrabursal injection of adenoviral Cre or inclusion of the MISR2-Cre transgene also resulted in augmented tumor growth. This finding suggests that follicle depletion provides a permissive ovarian environment for oncogenic transformation of epithelial cells, presenting a mechanism for the increased ovarian cancer risk in postmenopausal women.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ovarian Cancer Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Kathy Qi
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Smith
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Toni M
authors.initials: TM
authors.lastname: Yeasky
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Moore
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA Department of Pathology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Parvin
authors.initials: P
authors.lastname: Ganjei-Azar
authors.affiliation: Ovarian Cancer Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.affiliation: Ovarian Cancer Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Ovarian Cancer Programs, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Hamilton
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, USA xxu2@med.miami.edu.
authors.forename: Xiang-Xi
authors.initials: XX
authors.lastname: Xu
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D009154:Mutation; D009374:Neoplasms, Experimental; D006080:Ovarian Follicle / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D017698:Postmenopause; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C493961:Cdkn1b protein, mouse; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27