Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1 -mutated basal-like breast cancer

Abstract

Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are negative for hormone receptors and ERBB2, display frequent TP53 mutations, and express basal epithelial markers. To study the role of BRCA1 and P53 loss of function in breast cancer development, we generated conditional mouse models with tissue-specific mutation of Brca1 and/or p53 in basal epithelial cells. Somatic loss of both BRCA1 and p53 resulted in the rapid and efficient formation of highly proliferative, poorly differentiated, estrogen receptor-negative mammary carcinomas with pushing borders and increased expression of basal epithelial markers, reminiscent of human basal-like breast cancer. BRCA1-and p53-deficient mouse mammary tumors exhibit dramatic genomic instability, and their molecular signatures resemble those of human BRCA1-mutated breast cancers. Thus, these tumors display important hallmarks of hereditary breast cancers in BRCA1-mutation carriers.mouse models ͉ conditional knockout G erm-line mutations in the human breast cancer susceptibility gene BRCA1 are responsible for 40% to 50% of hereditary breast cancers and confer increased risk for development of ovarian, colon, and prostate cancers (1, 2). BRCA1 has been implicated in various cellular processes, including maintenance of genome integrity, DNA replication and repair, chromatin remodeling, and transcriptional regulation (3, 4). Although the exact mechanism of mammary tumor suppression by BRCA1 remains largely unknown, cells with dysfunctional BRCA1 show defects in survival and proliferation, increased radiosensitivity, chromosomal abnormalities, G 2 /M checkpoint loss, and impaired homologous recombination repair (5).BRCA1-mutated breast cancers that arise in women with germline mutations in BRCA1 are high-grade, hormone receptornegative breast carcinomas with frequent mutation of TP53 (4, 6). They also possess a basal-like phenotype as defined by the expression of markers that are typical for basal/myoepithelial cells, such as the basal cytokeratins (CKs) CK5/6 and CK14 (7). Indeed, strong molecular similarities are observed between hereditary BRCA1-mutated breast cancers and sporadic basal-like breast carcinomas (8,9). This phenotypic overlap has led to the hypothesis that sporadic basal-like cancers may have defects in BRCA1-related pathways, such as the amplification of EMSY and the methylation of BRCA1 and FANCF (10).Despite the fact that several mouse strains with conventional or conditional mutations in Brca1 have been generated (11), no good mouse model for BRCA1-mutated basal-like breast cancer has been developed so far. Most conventional Brca1 knockouts are embryonic-lethal when bred to homozygosity, yet heterozygous ⌬11 allele, which encodes BRCA1-⌬11, a naturally occurring splice variant of Brca1 (19). Mouse mammary tumor models ba...

BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

“…We next determined ROS levels in Brca1-deficient primary MECs (pMECs) using a previously generated Brca1 conditional knockout mouse (B1 f/f ) carrying a cre-inducible deletion of Brca1 exons 5-13 (Liu et al, 2007). Targeted Brca1 deletion to the mammary gland epithelium was achieved by crossing B1 f/f mice to K14cre mice (Jonkers et al, 2001) to obtain K14cre;Brca1 f/f mice (KB1 f/f ) along with K14cre (K) and K14cre;Bf/+ (KB1 f/+ ) control mice.…”

“…We used a Brca1 conditional knockout mouse (Liu et al, 2007) to specifically delete the Brca1 gene in the mammary gland. Although Brca1 deletion under the control of K14-or K6a-driven cre recombinase does not lead to any observable changes in the mammary gland (Liu et al, 2007;Smart et al, 2011), our study of primary and immortalized mouse and human BRCA1-deficient MECs shows that BRCA1 deficiency results in ROS accumulation in these cells. This effect When we evaluated Nrf2 expression in KB1 f/f pMECs, we found that both mRNA (Fig.…”

The emerging role of p53 in stem cells

“…Accordingly, p53 À/À mice, at least in the murine genetic background C57/BL6, rarely develop mammary tumors [34,[36][37][38][39]. Nevertheless, several observations suggest that loss of p53 is involved in the etiopathology of both human and mouse mammary tumors: (i) mutations of p53 are found in many breast cancers and women affected by the Li-Fraumeni syndrome (an inherited predisposition to cancer development linked to germline mutations in the p53 gene) often develop breast tumors [38]; (ii) in the BALB/c background, approximately 75% of p53 À/À mice have microscopic lesions in the mammary gland (sarcomas, epithelial hyperplasia and alterations in stromal morphology) [40]; (iii) transplantation of the p53 À/À BALB/c epithelium into fat pads of WT syngeneic mice leads to the development of mammary carcinomas in 60-75% of mice [40,41]; (iv) in a conditional mammary tumor model, approximately 70% of mice that carry tissue-specific inactivation of p53 develop mammary carcinomas [42]; and (v) in ErbB2 transgenic mice, which develop mammary carcinomas with high penetrance and short latency, p53 impairment is responsible for the immortal behavior and the geometric expansion of mammary CSCs in vitro and for carcinoma growth in vivo [34].…”

Xrcc2 Modulates Spontaneous and Radiation-Induced Tumorigenesis in Apcmin/+ Mice

“…The main type of mammary tumor found in the Apc min/+ Xrcc2 +/− mice was adenocarcinoma with squamous cell differentiation; similarly, this type of tumor was found in Brca1-or Brca2-compromised mice (23,24). These data suggest that Xrcc2 may act as a tumor suppressor following radiation damage, but in parallel to studies of mouse mutants of the Brca genes (25,26), further development of conditional and tissue-specific mouse Xrcc2 mutants would be required to support this finding.…”