Our findings have implications on the site

Our findings have implications on the site of origin of serous extra-uterine Müllerian carcinomas, which until recently were thought to originate primarily from metaplastic foci within the ovarian surface mesothelium (Dubeau, 1999, 2008). The fallopian tube is currently regarded as the most important site of origin of these tumors, the type associated with the BRCA1 mutation carrier state. We argued earlier that other extra-uterine Müllerian structures, including endosalpingiosis, endometriosis, and endocervicosis are also important in the histogenesis of the serous, endometrioid, and mucinous subtypes, respectively (Dubeau, 1999, 2008; Ahmed et al., 2010; Dubeau and Drapkin, 2013). All pelvic tumors seen in our mouse cohort appeared to have originated from endosalpingiosis, indicating that such extra-uterine structures are at risk of cancer development in mice carrying mutations mimicking those present in human with familial extra-uterine Müllerian carcinoma in support of our hypothesis.
In summary, we developed a mouse model that recapitulates the cell-autonomous and cell-nonautonomous mechanisms of cancer predisposition in human BRCA1 carriers. This model should facilitate elucidation of the menstrual factors associated with cell-nonautonomous mechanisms, which could represent attractive targets for cancer prevention strategies. Characterization of this model led to insights into the role of endosalpingiosis in the histogenesis of high grade serous extra-uterine Müllerian tumors, previously called ovarian, which should be considered in developing early detection and risk-reducing surgical strategies for these tumors. Our findings also shed light on the differentiation lineage of Müllerian clear cell carcinomas, which may facilitate the development of novel therapeutic approaches.

Funding Source Statement

Author\’s Contributions
Ying Liu developed the mouse model, made the Mis2r-Cre and Mis2r-Hsp68-LacZ constructs, maintained the mouse colonies, performed all autopsies, performed most of the experiments, and participated in the overall planning. Hai-Yun Yen performed the immunostains for purchase RG7112 and progesterone receptor proteins. Theresa Austria performed the studies on Her-2/neu expression. Jonas Pettersson performed studies on loss of heterozygosity. Janos Peti-Peterdi helped with the imaging studies of the kidney and helped in the redaction of the manuscript. Robert Maxson helped in the designing of the transgenic constructs and participated in the redaction of the manuscript. Martin Widschwendter helped in the analysis of the data and in the redaction of the manuscript. Louis Dubeau conceived and supervised the entire project and wrote the initial draft of the manuscript.

Acknowledgments
This work was aided by grants R01 CA119078 and R01 CA133117 from the US National Institutes of Health and by a gift from the Ovarian Cancer Coalition of Greater California to LD. Part of this work was funded by the Eve Appeal and undertaken at UCLH/UCL, which received a proportion of its funding from the Department of Health NIHR Biomedical Research Centers (BRC) funding scheme.

Introduction
Risk factors for breast cancer development include genetic predisposition and exposure to elevated sex steroid hormones. Germline mutations in BRCA1/2 account for elevated sex steroid hormones and 2%–10% of breast cancer cases depending on ethnic origin (Fackenthal and Olopade, 2007). Hormonal risk factors include early menarche, late menopause or first full pregnancy, weight gain, and combined hormone replacement therapy (HRT) (Veronesi et al., 2005). Evidence suggests a potential relationship between BRCA mutations, sex hormone levels, and end-organ effects to hormones, and cancer risk (Kim and Oktay, 2013; Segev et al., 2015; Titus et al., 2013; Widschwendter et al., 2013). High breast cancer risk in BRCA-mutation carriers is particularly evident premenopausally (relative risk 32 and 10 for 40–49-year-old BRCA1/2-mutation carriers, respectively) (Robson and Offit, 2007), whilst removal of both ovaries in premenopausal BRCA1/2-mutation carriers markedly reduces breast cancer risk (Domchek et al., 2010). Studies in BRCA1/p53-deficient mice indicate a direct role for progesterone (P) in mediating mammary tumourigenesis (Poole et al., 2006). Specific signalling pathways mediating interactions between BRCA-associated risk and sex steroid exposure have not been identified.