title: A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State.
abstract: Predisposition to breast and extrauterine Müllerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hormonal changes associated with the menstrual cycle. We used the Müllerian inhibiting substance type 2 receptor (Mis2r) promoter and a truncated form of the Follicle stimulating hormone receptor (Fshr) promoter to introduce conditional knockouts of Brca1 and p53 not only in mouse mammary and Müllerian epithelia, but also in organs that control the estrous cycle. Sixty percent of the double mutant mice developed invasive Müllerian and mammary carcinomas. Mice carrying heterozygous mutations in Brca1 and p53 also developed invasive tumors, albeit at a lesser (30%) rate, in which the wild type alleles were no longer present due to loss of heterozygosity. While mice carrying heterozygous mutations in both genes developed mammary tumors, none of the mice carrying only a heterozygous p53 mutation developed such tumors (P < 0.0001), attesting to a role for Brca1 mutations in tumor development. This mouse model is attractive to investigate cell-nonautonomous mechanisms associated with cancer predisposition in BRCA1 mutation carriers and to investigate the merit of chemo-preventive drugs targeting such mechanisms.
authors.affiliation: Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Yen
authors.affiliation: Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Theresa
authors.initials: T
authors.lastname: Austria
authors.affiliation: Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Jonas
authors.initials: J
authors.lastname: Pettersson
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Maxson
authors.affiliation: Department of Women's Cancer, University College London, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.affiliation: Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055786:Gene Knockout Techniques; D019398:Genes, BRCA1; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009095:Mullerian Ducts / Q000196:embryology / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D038081:Organogenesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011962:Receptors, FSH / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011962:Receptors, FSH; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C084621:anti-Mullerian hormone receptor
keywords: Brca1; Cell non-autonomous mechanism of cancer predisposition; Familial cancer predisposition; Mouse model of breast and ovarian cancer; Müllerian inhibiting substance