BRCA1 Mutations in Cancer: Coordinating Deficiencies in Homologous Recombination with Tumorigenesis

Abstract

Cancers that arise from BRCA1 germline mutations are deficient for homologous recombination (HR) DNA repair and are sensitive to DNA-damaging agents such as platinum and PARP inhibitors. In vertebrate organisms, knockout of critical HR genes including BRCA1 and BRCA2 is lethal because HR is required for genome replication. Thus, cancers must develop strategies to cope with loss of HR activity. Furthermore, as established tumors respond to chemotherapy selection pressure, additional genetic adaptations transition cancers to an HR-proficient state. In this review, we discuss biological mechanisms that influence the ability of BRCA1-mutant cancers to perform HR. Furthermore, we consider how the HR status fluctuates throughout the cancer life course, from tumor initiation to the development of therapy refractory disease.

Figure 1.

Schematic representation of BRCA1 full-length and hypomorphic proteins that have been detected in cancers. (A) The full-length (p220) BRCA1 protein is depicted along with known functional domains and corresponding protein interactions. Amino acid (aa) residues corresponding to predicted domain start and end sites are indicated as well as potential functional activities of each domain. (B) BRCA1 cDNA is shown (above) with corresponding base pairs indicated. Redlines indicate regions where frameshift mutations may be present but remain capable of expressing either the BRCA1-ΔRING, BRCA1-Δ11q, or BRCA1-ΔBRCT proteins.

Figure 2.

The HR spectrum over the life course of a BRCA1 mutant cancer. Partial HR activity is likely required for tumor initiation and growth, but may also play a role in therapy resistance, and could account for some patients demonstrating poor responses in the treatment naïve setting. Dashed line indicates HR activity and solid line indicates cancer growth over time. Arrows along the x axis indicate significant events over the course of cancer development and progression. Shading colors correspond to cancer development, cancer growth, PARPi and Platinum therapy (P+P) responsiveness and resistant growth.