Abstract
Inactivation of the breast cancer susceptibility gene 1 (BRCA1) plays a significant role in the development of a subset of familial breast and ovarian cancers, but increasing evidence points to a role also in sporadic tumors. BRCA1 is a multifunctional nuclear protein involved in the regulation of many nuclear cellular processes, including DNA repair, cell cycle, transcription and chromatin remodeling. To identify novel proteins participating in the BRCA1 network, two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry were used to compare the nuclear-enriched proteome map of BRCA1-deficient and BRCA1-proficient cell lines. Five differentially expressed polypeptides were identified and two of them, hnRNPA2B1 and KHSRP, turned out to be involved in mRNA and miRNA metabolism. qRT-PCR analyses indicated that the hnRNPA2B1 and KHSRP levels increased in response to BRCA1 loss and restoration of BRCA1 expression in BRCA1 null cells reverted hnRNPA2B1 and KHSRP up-regulation. Interrogation of publicly available transcriptional profiling datasets revealed that both genes were actually over-expressed in BRCA1 mutated tumors. Overall, our results indicate that BRCA1 modulates the expression of two proteins involved in the processing of RNA, highlighting the complex nature of BRCA1-associated tumor suppressor function and disclosing a novel mechanism by which BRCA1 may affect transcription.