Abstract 3254: Characterization of two mutant models with distinct expression profile of BRCA1 splice variant IRIS

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC More than 400 cancer-associated Brca1 mutations have been discovered and it is reported that different mutations in the Brca1 gene confer different cancer-related phenotypes. An important aspect that has complicated proper interpretation of the various Brca1 mutants in human and mouse model is the fact that Brca1 transcripts are subject to alternative splicing. In humans, two splice variants (Brca1-Δ11 and Brca1-IRIS) have been functionally analyzed to date. Unlike full-length Brca1, BRCA1-IRIS although largely encoded by identical sequences behaves more like a proto-oncogene. To investigate the function of the BRCA1-IRIS allele in vivo, we studied growth and tumorigenesis in Brca1F22–24 mice which express a BRCA1-IRIS and compared the phenotype directly to the Brca1F5–13 model that is functionally null for all BRCA1 activity. Brca1−/−;p53+/−;K14Cre mice generated from both Brca1 alleles showed a phenotype of premature aging. Alopecia was developed at average 12 and 20 wks of age in Brca1F5–13/F5–13;p53+/−;K14Cre and Brca1F22–24/F22–24;p53+/−;K14Cre genotypes respectively. Mammary glands from Brca1F5–13/F5–13;p53+/−;K14Cre mice displayed ductal dysplasia. This ductal abnormality was also observed in Brca1F22–24/F22–24;p53+/−;K14Cre mice. But in contrast to the Brca1F5–13 allele, gland from these mice showed ductal hyperplasia. Mammary tumors developed only in the Brca1F22–24/F22–24;p53+/−;K14Cre mice with high frequency. However, Brca1F5–13/ F5–13;p53+/−;K14Cre mice never developed tumors possibly due to severe aging process taken place before full mammary development. MEF cells generated from two transgenic models also showed different features in their growth and cell cycle. Brca1 abrogation retarded cell growth by arresting cells in G2/M phase. Arrested cell fraction was higher in MEF cells obtained from Brca1F22–24/ F22–24 mouse compared to one from Brca1F5–13/ F5–13 mouse. Consequently Brca1F22–24/ F22–24 MEF cells were more sensitive to M phase specific inhibitor vinorelbine. Different Brca1 mutations that encode truncated version of full length protein could, in theory, still able to produce other Brca1 splice variants. Various genotype-phenotype correlations found in different Brca1 mutation carrier are likely to be caused by different expression profiles of Brca1 splice variants. Our study, using two different Brca1 mutant models that show distinct expression of Brca1-IRIS, is first attempt to distinguish different Brca1 knock out models regarding Brca1 splice variant. Further investigation of this new aspect of BRCA1 biology will help us to understand different functions exerted by distinct BRCA1 splice variants. Our study could have important implications for genetic counseling and treatment of carriers having different type of Brca1 mutation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3254.