Mechanisms of BRCA1 tumor suppression

Abstract

The p220 BRCA1 tumor suppressor protein has been implicated in multiple biochemical and biologic functions since its molecular cloning 18 years ago. Here, we discuss those functions most relevant for its tumor-suppressing activities with an emphasis on new findings. In particular, this review focuses on what is known of the activities of those BRCA1-binding partners that have tumor suppressor functions, on the reversion of mutant BRCA1 alleles concomitant with therapy resistance, on insights gained from studies of BRCA1 structure-function relationships, recent findings from animal models, and the potential role of BRCA1 in some nonhereditary tumors. From this information, a more detailed and refined picture of BRCA1 tumor suppression is beginning to emerge. Although key mysteries remain--such as why BRCA1 tumor suppression is focused on carcinomas of the breast and ovary--the pace of discovery is increasing.

Significance: BRCA1 functions as a clinically important classical tumor suppressor in hereditary breast and ovarian cancer; here, we review progress in understanding how BRCA1 operates to suppress tumor formation.

Figure

The domain structure of BRCA1 is shown, with the RING domain in blue, the tandem nuclear localization signals in yellow, the Coiled-coil domain in green, and the two BRCT domains in red. Amino acid locations of mutations referred to in the review are as shown.