How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility?

The inheritance of monoallelic germline mutations affecting BRCA1 or BRCA2 predisposes with a high penetrance to several forms of epithelial malignancy. The large, nuclear-localized BRCA proteins act as custodians of chromosome integrity through distinct functions in the assembly and activity of macromolecular complexes that mediate DNA repair, replication reactivation and mitotic progression. The loss of these tumour suppressive functions following biallelic BRCA gene inactivation has long been thought to provoke genomic instability and carcinogenesis. However, recent studies not only identify new functions for BRCA1 and BRCA2 in the regulation of transcription and RNA processing potentially relevant to their tumour suppressive activity, but also suggest that monoallelic BRCA2 gene mutations suffice for carcinogenesis. This emerging evidence opens fresh lines of enquiry concerning tissue-specific cancer evolution in BRCA mutation carriers. Collectively, these insights engender new models to explain how BRCA gene mutations cause cancer susceptibility in specific tissues.