A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State
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 hormona...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-10-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396415301171 |
| _version_ | 1819078252518440960 |
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| author | Ying Liu Hai-Yun Yen Theresa Austria Jonas Pettersson Janos Peti-Peterdi Robert Maxson Martin Widschwendter Louis Dubeau |
| author_facet | Ying Liu Hai-Yun Yen Theresa Austria Jonas Pettersson Janos Peti-Peterdi Robert Maxson Martin Widschwendter Louis Dubeau |
| author_sort | Ying Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T19:10:08Z |
| format | Article |
| id | doaj.art-46eb1f5f37d245b7b54ad8195794fba6 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-21T19:10:08Z |
| publishDate | 2015-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-46eb1f5f37d245b7b54ad8195794fba62022-12-21T18:53:13ZengElsevierEBioMedicine2352-39642015-10-012101318133010.1016/j.ebiom.2015.08.034A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier StateYing Liu0Hai-Yun Yen1Theresa Austria2Jonas Pettersson3Janos Peti-Peterdi4Robert Maxson5Martin Widschwendter6Louis Dubeau7Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United StatesDepartment of Biochemistry and Molecular Biology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United StatesDepartment of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United StatesDepartment of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United StatesDepartment of Physiology and Biophysics, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United StatesDepartment of Biochemistry and Molecular Biology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United StatesDepartment of Women's Cancer, University College London, London, UKDepartment of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90089, United StatesPredisposition 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.http://www.sciencedirect.com/science/article/pii/S2352396415301171Brca1Familial cancer predispositionMüllerian inhibiting substanceMouse model of breast and ovarian cancerCell non-autonomous mechanism of cancer predisposition |
| spellingShingle | Ying Liu Hai-Yun Yen Theresa Austria Jonas Pettersson Janos Peti-Peterdi Robert Maxson Martin Widschwendter Louis Dubeau A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State EBioMedicine Brca1 Familial cancer predisposition Müllerian inhibiting substance Mouse model of breast and ovarian cancer Cell non-autonomous mechanism of cancer predisposition |
| title | A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State |
| title_full | A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State |
| title_fullStr | A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State |
| title_full_unstemmed | A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State |
| title_short | A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State |
| title_sort | mouse model that reproduces the developmental pathways and site specificity of the cancers associated with the human brca1 mutation carrier state |
| topic | Brca1 Familial cancer predisposition Müllerian inhibiting substance Mouse model of breast and ovarian cancer Cell non-autonomous mechanism of cancer predisposition |
| url | http://www.sciencedirect.com/science/article/pii/S2352396415301171 |
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