BRCA1, BRCA2, and hereditary breast cancer

I. INTRODUCTION The etiology of breast cancer is multifactorial, involving environmental factors, hormones, genetic susceptibility, and genetic changes during progression. Mutations in a number of genes are known to cause susceptibility to breast cancer. In the context of high-risk breast and ovarian cancer families, the most notorious genes are BRCA1 and BRCA2. As suggested by numerous studies, this disease in most families with multiple cases of breast and ovarian cancer and most but not all very large families with multiple cases of breast cancer appears to be associated with mutations in BRCA1 and BRCA2. The BRCA1 and BRCA2 genes encode for large nuclear proteins. Traditional protein motifs are not common in either of these expansive proteins; therefore few clues have been found regarding their biological or biochemical functions by sequence analysis. Hundreds of mutations have been identified throughout both genes; however, these observations have failed to identify any single critical functional domain. Scientists have taken many approaches to help uncover the potential function of BRCA1 and BRCA2 and have made substantial strides since the genes were first identified in the mid-1990s. Unfortunately, despite recent efforts and scientific accomplishments, there are still more questions than answers. For example, are BRCA1 and BRCA2 classic tumor suppressors, and why do mutations in these genes primarily predispose to breast and/or ovarian cancer? In this chapter, we describe what is currently known about the biological and biochemical functions of BRCA1 and BRCA2 and speculate on how mutations in these essential genes contribute to the development of breast and other cancers.