New insights into BRCA1 function and its role in cancer development

BRCA1 is a breast and ovarian tumor suppressor. The role of BRCA1 in the repair of double strand DNA breaks by homologous recombination [HR] is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. However, BRCA1 has less well defined roles in multiple other molecular processes.;Given its numerous, incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein interacting partners and functions. We detected a new function for BRCA1 in the response to transcription-associated DNA damage, based on the screening results. Genetic interactions were detected between BRCA1 and four of the newly identified interacting proteins [interactors] involved in transcription, TONSL, SETX, TCEANC, and TCEA2, and with specific interactors of one of these proteins. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is aberrant in both breast and ovarian cancers.;These findings may be particularly meaningful with respect to the sporadic basal-like breast cancer [BLC] subtype. This common subtype shares multiple biological properties with BRCA1 mutated breast tumors. Despite being BRCA1+/+, sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers and are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway[s] in which BRCA1 plays a major role. Given that the BRCA1 role in HR is its best understood function, it is suspected that sporadic BLC exhibit an HR defect.;To test this hypothesis and to search for other BRCA1 pathway defects, multiple HR assays were performed on a group of cell lines classified as sporadic BLC and on controls. The sporadic BLC lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks and potentially damage associated with stalled transcription, a new BRCA1 function.;These results provide insight into why clinical trials of PARP inhibitors, which require HR defects for efficacy, have been unsuccessful in sporadic BLC, unlike cisplatin which elicits stalled replication and transcription fork repair and has shown efficacy in sporadic BLC.