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.

Pathogenesis and heterogeneity of ovarian cancer

“…In particular, several mouse models were created by genetically manipulating murine oviductal cells [58–62]. Some of these models have recapitulated the development of tubal precursor lesions [58,60] and demonstrated that salpingectomy blocks tumor development [58,61].…”

Responsiveness of Brca1 and Trp53 Deficiency–Induced Mammary Preneoplasia to Selective Estrogen Modulators versus an Aromatase Inhibitor in Mus musculus

“…Published work documents that disruption of Trp53 frequently occurs in breast cancers that develop in women carrying BRCA1 mutations (18), contributes to cancer generation in mice with disrupted Brca1 alleles (12,14,19,30), and by itself does not lead to mammary cancer by age 12 months (16). Like Brca1 fl11/fl11/Cre/p53−/+ mice, Brca1 WT/fl11/Cre/p53−/+ mice developed invasive mammary cancer by age 12 months without significant difference in latency (Fig.…”

“…Here we tested the impact of antihormonals on preneoplasia development with both one and two Brca1 alleles and found evidence of increased responsiveness to tamoxifen in Brca1 WT/fl11/Cre/p53−/+ as compared to Brca1 fl11/fl11/Cre/p53−/+ mice. There has been significant discussion around whether or not Brca1 LOH is required for cancer development (18,19). Significantly we determined that Brca1 LOH was not required for mammary cancer development and found no evidence that Trp53 LOH was required for cancer development even though this has been previously reported for this model (22).…”

“…Trp53 heterozygosity has been observed to be obligatory for mammary cancer generation in GEMM with both one and two Brca1 alleles disrupted (12,19). Loss of Phosphatase And Tensin Homolog ( PTEN) (18) , pathogenic mutations in Death-Associated Protein Kinase 3 ( DAPK3 ), Transmembrane Protein 135 ( TMEM135 ) , and GATA Binding Protein 4 ( GATA4 ) (20), and kindreds showing mutation in both BRCA1 and Breast Cancer 2 ( BRCA2 ) (21) have been reported to contribute to human breast cancer generation.…”

Mechanism of cytokinesis failure in ovarian cystadenomas with defective BRCA1 and P53 pathways

“…This chain of events can lead to spontaneous malignant transformation and, in fact, led to the establishment of immortal cell lines in our laboratory. 10 We hypothesize, based on observations not only with this in vitro model, but also with mice carrying a conditional Brca1 knockout 16 as well as observations with human populations, 17,18 that the molecular events mediating predisposition to triple negative breast carcinoma and high-grade serous extra-uterine Müllerian carcinoma in BRCA1 mutation carriers entail an interplay between cell-nonautonomous consequences of this carrier state in ovarian granulosa cells resulting in increased cellular proliferation and, thus, premature aging in mammary and extra-uterine Müllerian epithelia, and cellautonomous consequences leading to numerical chromosomal abnormalities in these epithelia due to cytokinesis failure associated with advanced replicative ages. 14 We sought to better understand the mechanism underlying the prolonged arrest at the spindle assembly checkpoint associated with increased replicative age, which is a central element of this proposed interplay between cell-autonomous and -nonautonomous mechanisms of cancer predisposition, in an effort to gain insights into the molecular events associated with early cancer development in individuals with germline BRCA1 mutations.…”