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 of BRCA1 was shown to induce an apoptotic signaling pathway involving the c-Jun N-terminal kinase (JNK), but the signaling steps upstream and downstream of JNK were not delineated. To better understand the role of BRCA1 in apoptosis, we examined the effect of wild-type and C-terminal-truncated dominant negative BRCA1 on breast and ovarian cancer cell lines subjected to a number 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 BRCA1 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. In addition, the pathway functioned independently of the p53 tumor suppressor. 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 mutations may contribute to tumor development.
Departments of Laboratory Medicine and Pathology, Oncology, Molecular Pharmacology, and Biochemistry and Molecular Biology Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
M
M
Thangaraju
S H
SH
Kaufmann
F J
FJ
Couch
D017209:Apoptosis; D019313:BRCA1 Protein / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D020169:Caspases / Q000502:physiology; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000502:physiology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D019014:fas Receptor / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
D019313:BRCA1 Protein; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; C482779:MAP3K4 protein, human; D020169:Caspases; D018631:ras Proteins