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R.E. Mansel et al. (eds.), Metastasis of Breast Cancer, 31-46. © 2007 Springer.

1. BRCA1: A TISSUE-SPECIFIC TUMOR SUPPRESSOR GENE

Breast cancer susceptibility gene BRCA1 was identified in 1994 through genetic linkage analysis and positional cloning (1, 2). Germ-line mutations of BRCA1 occur at a frequency of approximately 1 in 250 women, and these mutations account for 45% of the familial breast cancer and 80-90% of the hereditary cases where both breast and ovarian cancers occur (breast-ovarian cancer syndrome) (3-5). Genetic analysis of BRCA1-associated tumor specimens strongly indicate that BRCA1 functions as a tumor suppressor, as the tumors invariably lose the wild-type copy of BRCA1 and retain the inherited mutant copy (loss of heterozygosity; LOH). However, in contrast to mutations of other well-defined tumor suppressor genes such as p53, somatic mutations in the BRCA1 coding region are rarely found in sporadic breast or ovarian cancers. Nevertheless, reduced expression of BRCA1 mRNA, and protein has been observed in a significant percentage (30-40%) of sporadic breast/ovarian cancer cases; and this is particularly true in tumors with high nuclear grade (6-8). Furthermore, promoter hypermethylation-mediated gene silencing of the BRCA1 locus occurs in 10-15% of sporadic breast and ovarian cancer cases (9-11), supporting the notion that BRCA1 may also play a role in suppression of sporadic breast cancer. In a recent comprehensive analysis of cancer risks among BRCA1 mutation-carriers, it was shown that this group of women has 80% chance of developing breast cancer in their lifetime (12). Interestingly, the same study also found that physical exercise and lack of obesity in adolescence significantly delay the onset of BRCA1 -associated breast cancer, which underscores the importance of nongenetic factors in cancer prevention.

Figure 1. Diagram of the BRCA1 protein. The structural motifs including the RING and BRCT domains are highlighted. Also listed is a subset of BRCA1-interacting proteins.
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