title: Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs.
abstract: Incessant menstrual cycle activity, uninterrupted by either pregnancy or oral contraceptive use, is the most important risk factor for sporadic ovarian cancer. Menstrual cycle progression is partly controlled by steroid hormones such as estrogens and others that are secreted by the ovarian granulosa cells. We showed earlier that mice carrying a homozygous granulosa cell-specific knockout of Brca1, the homolog of BRCA1 that is associated with familial ovarian cancer predisposition in humans, develop benign epithelial tumors in their reproductive tract. These tumors are driven, at least in part, by a prolongation of the proestrus phase of the estrus cycle (equivalent to the follicular phase of the menstrual cycle) in Brca1 mutant mice, resulting in prolonged unopposed estrogen stimulation. Mutant mice synchronized in proestrus also showed increased circulating estradiol levels, but the possibility that this change also has a role in tumor predisposition was not investigated. We sought to determine whether these changes in hormonal stimulation result in measurable changes in tissues targeted by estrogen outside the ovary. Here we show that mice carrying a Brca1 mutation in their ovarian granulosa cells show increased endometrial proliferation during proestrus, implying that the effects of Brca1 inactivation on estrogen stimulation have short-term consequences, at least on this target organ. We further show that mutant mice develop increased femoral trabecular thickness and femoral length, which are well-known consequences of chronic estrogen stimulation. Estrogen biosynthesis by granulosa cells was increased not only in mice carrying a homozygous Brca1 mutation, but also in heterozygous mutants mimicking the mutational status in granulosa cells of human BRCA1 mutation carriers. The results suggest that human germline BRCA1 mutations, although associated with increased cancer risk, may also have beneficial consequences, such as increased bone strength, that may have contributed to the maintenance of mutated BRCA1 alleles in the human gene pool.
authors.affiliation: Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Yen
authors.forename: Yankel
authors.initials: Y
authors.lastname: Gabet
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Anthony
authors.initials: A
authors.lastname: Martin
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Wu
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
authors.forename: Robert
authors.initials: R
authors.lastname: Maxson
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001141:Aromatase / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004717:Endometrium / Q000254:growth & development* / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000096:biosynthesis; D030762:Estrous Cycle / Q000097:blood / Q000235:genetics*; D004973:Estrus Synchronization / Q000502:physiology; D005260:Female; D005269:Femur / Q000378:metabolism / Q000473:pathology; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006107:Granulosa Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D019313:BRCA1 Protein; D004967:Estrogens; D004958:Estradiol; D001141:Aromatase