| Summary: | 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. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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