BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines

The BRCA1 tumor suppressor gene has previously been implicated in induction of high levels of apoptosis in osteocarcinoma cell lines. Overexpression o f BRCA1 was shown to induce an apoptotic signaling pathway involving the c- Jun N-terminal kinase (JNK), but the signaling steps upstream and downstrea m of JNK were not delineated. To better understand the role of BRCA1 in apo ptosis, we examined the effect of wild-type and C-terminal-truncated domina nt negative BRCA1 on breast and ovarian cancer cell lines subjected to a nu mber of different pro-apoptotic stimuli, including growth factor withdrawal , substratum detachment, ionizing radiation, and treatment with anticancer agents. All of these treatments were found to induce substantial levels of apoptosis in the presence of wild-type BRCA1, whereas dominant negative BRC A1 truncation mutants diminished the apoptotic response. Subsequent mapping of the apoptotic pathway induced by growth factor withdrawal demonstrated that BRCA1 enhanced signaling through a pathway that sequentially involved H-Ras, MEKK4, JNK, Fas ligand/Fas interactions, and caspase-9 activation. I n addition, the pathway functioned independently of the p53 tumor suppresso r. These data suggest that BRCA1 is an important modulator of the response to cellular stress and that loss of this apoptotic potential due to BRCA1 m utations may contribute to tumor development.