Women with germline mutations in BRCA1 are strongly predisposed to cancers of the ovary and fallopian tubes. Extensive epidemiological data have demonstrated a strong link between menstrual activity and risk of ovarian cancer in the general population. This led us to hypothesize that BRCA1 might predispose to ovarian cancer indirectly, by influencing ovarian granulosa cells, which play an important role in controlling menstrual cycle progression through their secretion of sex steroid hormones. Such hormones, as well as the peptide hormone mullerian inhibiting substance (MIS), also secreted by granulosa cells, can regulate ovarian epithelial tumor cell growth. We used the Cre-lox system to inactivate the mouse Brca1 gene in granulosa cells in order to test this hypothesis. A truncated form of the FSH receptor promoter, which directs expression exclusively in granulosa cells, was used as Cre driver. A majority (40/59) of Brca1 knockout mice had grossly visible cystic tumors either attached to the ovary, to the uterine horns, or with no demonstrable attachment to either of these organs. All tumors except one resembled human serous cystadenomas, which are benign tumors made up of the same cell type as ovarian serous carcinomas. A single tumor was histologically compatible with malignancy, although no sign of invasive or metastatic ability could be demonstrated. Strikingly, these tumors carried only the non-recombined (wild type) form of the floxed BRCA1 allele while the recombined (mutant) form was present only in granulosa cells in strong support of our hypothesis. Our proposal is focused on the elucidation of the mechanism of tumor predisposition in this experimental model, which we believe to be relevant to the strong tumor predisposition seen in women with germline BRCA1 mutations. We will identify the nature and tissue distribution of the ovarian and uterine cells affected by an absence of functional Brca1 in granulosa cells and will evaluate the reversibility of the phenotypic consequences of such defect and the protective role of pregnancy in Aim 1. We will characterize the consequences of such absence on the timing and hormonal activity of the various phases of the ovulatory cycle in Aim 2. The consequences of absence of a functional Brca1 on the spectrum of gene expression in ovarian granulosa cells will be examined in the last aim (Aim 3). Once the mechanisms of tumor predisposition are understood in this experimental model, we will be in a position to investigate its relevance to humans carrying a germline BRCA1 mutation and to use this knowledge to develop novel approaches to the clinical management of these individuals. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119078-02
Application #
7262506
Study Section
Special Emphasis Panel (ZRG1-ONC-L (03))
Program Officer
Mietz, Judy
Project Start
2006-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$224,748
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Liu, Ying; Yen, Hai-Yun; Austria, Theresa et al. (2015) A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State. EBioMedicine 2:1318-30
Liu, Ying; Pike, Malcolm C; Wu, Nancy et al. (2015) Brca1 Mutations Enhance Mouse Reproductive Functions by Increasing Responsiveness to Male-Derived Scent. PLoS One 10:e0139013
Widschwendter, Martin; Rosenthal, Adam N; Philpott, Sue et al. (2013) The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. Lancet Oncol 14:1226-32
Dubeau, L; Drapkin, R (2013) Coming into focus: the nonovarian origins of ovarian cancer. Ann Oncol 24 Suppl 8:viii28-viii35
Yu, Vanessa M; Marion, Christine M; Austria, Theresa M et al. (2012) Role of BRCA1 in controlling mitotic arrest in ovarian cystadenoma cells. Int J Cancer 130:2495-504
Yen, Hai-Yun; Gabet, Yankel; Liu, Ying et al. (2012) Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs. Lab Invest 92:802-11
Hong, Hao; Yen, Hai-Yun; Brockmeyer, Amy et al. (2010) Changes in the mouse estrus cycle in response to BRCA1 inactivation suggest a potential link between risk factors for familial and sporadic ovarian cancer. Cancer Res 70:221-8
Dubeau, Louis (2008) BRCA1-induced ovarian oncogenesis. Adv Exp Med Biol 622:89-97
Dubeau, Louis (2008) The cell of origin of ovarian epithelial tumours. Lancet Oncol 9:1191-7
Yu, J; Roy, D; Brockmeyer, A D et al. (2007) Increased chromosomal stability in cultures of ovarian tumours of low malignant potential compared to cystadenomas. Br J Cancer 96:1908-13