title: Granulosa Cell-Specific Brca1 Loss Alone or Combined with Trp53 Haploinsufficiency and Transgenic FSH Expression Fails to Induce Ovarian Tumors.
abstract: BRCA1 mutations are associated with ovarian cancer. Previous studies reported that murine granulosa cell (GC) Brca1 loss caused ovarian-uterine tumors resembling serous cystadenomas, but the pathogenesis of these tumors may have been confounded by ectopic Brca1 expression and altered estrous cycling. We have used Tg.AMH.Cre conferring proven ovarian and GC-specific Cre activity to selectively target Brca1 disruption, denoted Brca1(GC-/-). Furthermore, ovary-specific Brca1(GC-/-) was combined with global Trp53 haploinsufficiency (Trp53(+/-)) and transgenic follicle-stimulating hormone (Tg.FSH) overexpression as a multi-hit strategy to investigate additional genetic and hormonal ovarian tumorigenesis mechanisms. However, 12-month-old Brca1(GC-/-) mice had no detectable ovarian or uterine tumors. Brca1(GC-/-) mice had significantly increased ovary weights, follicles exhibiting more pyknotic granulosa cells, and fewer corpora lutea with regular estrous cycling compared to controls. Isolated Brca1(GC-/-) mutation lengthened the estrous cycle and proestrus stage; however, ovarian cystadenomas were not observed, even when Brca1(GC-/-) was combined with Trp53(+/-) and overexpressed Tg.FSH. Our Brca1(GC-/-) models reveal that specific intra-follicular Brca1 loss alone, or combined with cancer-promoting genetic (Trp53 loss) and endocrine (high serum FSH) changes, was not sufficient to cause ovarian tumors. Our findings show that the ovary is remarkably resistant to oncogenesis, and support the emerging view of an extragonadal, multi-hit origin for ovarian tumorigenesis.
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW, 2139, Australia.
authors.forename: Dannielle H
authors.initials: DH
authors.lastname: Upton
authors.forename: Emily S
authors.initials: ES
authors.lastname: Fuller
authors.forename: Emily K
authors.initials: EK
authors.lastname: Colvin
authors.forename: Kirsty A
authors.initials: KA
authors.lastname: Walters
authors.forename: Mark
authors.initials: M
authors.lastname: Jimenez
authors.forename: Reena
authors.initials: R
authors.lastname: Desai
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.forename: Viive M
authors.initials: VM
authors.lastname: Howell
authors.forename: Charles M
authors.initials: CM
authors.lastname: Allan
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics*; D003537:Cystadenoma / Q000235:genetics / Q000473:pathology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000235:genetics* / Q000378:metabolism; D006107:Granulosa Cells / Q000378:metabolism; D057895:Haploinsufficiency; D051379:Mice; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D010053:Ovary / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014599:Uterus / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D005640:Follicle Stimulating Hormone