Analysis of tumor suppressor genes for breast cancer

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Mutations in the BRCA1 and BRCA2 genes are involved in approximately 60% of familial breast cancers and these results indicate the existence of the 3rd major gene responsible for hereditary breast cancers. The isolation of this gene is important for the genetic testing of hereditary breast cancer. The yeast two-hybrid system was used to isolate BRCA2-binding proteins. We showed that BRCA2 formed a complex with Rad51 and the pattern of northern blot analysis of the Rad51 genewas closely similar to that of the BRCA2 gene. It is therefore possible that alterations of the Rad51 gene may be involved in the development of hereditary breast cancers. To investigate this possibility, we screened Japanese patients with hereditary breast cancer for Rad51 mutations and found a single alteration in exon 6. This was determined to be present in the germline in two patients with bilateral breast cancer. In both patients, blood DNAs showed G-to-A transition of the second nucleotide of codon 150, which … More results in the substitution of glutamine for arginine. Since this alteration was not present in patients with breast or colon cancer examined, we assume that this missense alteration is likely to represent a disease-associated mutation. Another candidate of BRCA2-binding protein, designated BRAP1, is highly homologous to Amphiphysin and BIN1, that were reported to be associated with breast carcinogenesis. The exon-intron boundaries of this gene were determined, and screening for germline mutation in breast cancer families and for somatic mutation in primary breast cancers was performed. Although no mutation was found in families and primary cancers, the expression level of the BRAP1 gene was detected to be remarkably decreased in breast cancer cell lines and pancreas cancer cell lines.We have described the possibility that a small portion of bilateral breast cancers is due to germline alterations of Rad51. However, the 3rd major breast cancer susceptibility gene remains unknown ; intense efforts will be required to isolate the gene (s) responsible. Less