Brca1 in development and tumorigenesis

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In the past year, we generated and analyzed a mouse model carrying a mutation that blocks the slicing between BRCA1 exons 10 and 11. Alternative splicing in the BRCA1 locus generates multiple protein products including BRCA1-Delta11, which is identical to the BRCA1 full-length isoform (BRCA1-FL) except for the absence of exon 11. To understand the physiologic functions of BRCA1-Delta11, we used a knock-in approach that blocks alternative splicing between exons 10 and 12 to prevent the formation of this form of BRCA1. We showed that homozygous mutant mice (Brca1(FL/FL)) were born at a Mendelian ratio without obvious developmental defects. However, the majority of Brca1(FL/FL) female mice showed mammary gland abnormalities and uterine hyperplasia after one year of age with spontaneous tumor formation. Cultured Brca1(FL/FL) cells exhibited abnormal centrosome amplification and reduction of G(1) population that was accompanied by accumulation of cyclin E and cyclin A. Accumulation of cyclin E was also found in epithelial layers of dilated ducts and hyperproliferative lobular regions in the mammary glands of Brca1(FL/FL) mice. These observations provide evidence that BRCA1 splicing variants are involved in BRCA1 functions in modulating G(1)/S transition, centrosome duplication, and repressing tumor formation. Thus, together with mutant mice generated earlier, we have generated and reported a total of five mutant models for BRCA1, including two null mutations, one conditional mutation, two isoform mutations and one point mutation. Our studies using these models demonstrate that BRCA1 plays essential functions in many biological processes, including transcription regulation, cell cycle progression, apoptosis, DNA damage repair, centrosome duplication and animal aging.