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UBC Theses and Dissertations

The investigation of a novel BRCA2-associated gene, EMSY, on chromosome 11Q13 in breast and ovarian cancer Brown, Lindsay Anne


EMSY is a novel gene encoding a protein that binds to the tumor suppressor BRCA2. EMSY maps to 11q13, a region commonly amplified in breast cancer, and is located 6 Mb telomeric to CCND1. However, the role of EMSY amplification in breast and ovarian cancer is largely unknown. Here we present evidence that EMSY is commonly amplified in breast cancer, and associated with a poor outcome in several pathological subsets of breast cancer. EMSY gene amplification is a less common event in BRCA2 mutation carriers, providing evidence to support the potential role o f EMSY as surrogate for BRCA2 loss in sporadic breast cancer. In ovarian cancer, EMSY amplification is associated with high grade ovarian carcinomas, and is a frequently amplified element o f the 11q13 amplicon in ovarian cancer. A more detailed analysis of the 11q13 amplicon, which harbors numerous oncogenes including CCND1, EMSY, PAK1, Rsf-1, and GAB2, demonstrated that all five genes are frequently amplified in ovarian carcinomas and are specifically associated with serous carcinomas. Lastly, we wanted to determine whether EMSY overexpression shares similar biological features with loss o f BRCA2 function. Overexpression of a 5' fragment of EMSY induces a chromosomal instability phenotype in human breast epithelial cells that is similar to that of BRCA2 deficient cells. Furthermore, treatment with the DNA damaging agent mitomycin C produced a several fold higher frequency of chromosome breaks in the EMSY overexpressing cells than in the control cells. Overexpression of the 5' fragment o f EMSY did not induce a chromosomal instability phenotype in two immortalized normal ovarian surface epithelial cell lines even after treatment with mitomycin C, suggesting that these cells may not be the correct cell type in which to study EMSY overexpression. EMSY overexpressing breast epithelial cells did not exhibit increased sensitivity to treatment with the DNA damaging agents, doxorubicin and cisplatin, suggesting that EMSY may not play a role in the direct repair of DNA double stranded breaks. In conclusion, these results demonstrate that EMSY amplification is a clinically significant event in breast and ovarian cancer, and elevated levels of EMSY may play a role in sporadic breast carcinogenesis by deregulating protection of genomic stability.

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