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

Muthusamy Thangaraju, Scott H. Kaufmann, Fergus J. Couch

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)33487-33496
Number of pages10
JournalJournal of Biological Chemistry
Volume275
Issue number43
DOIs
StatePublished - Oct 27 2000
Externally publishedYes

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Ovarian Neoplasms
Tumors
Cells
Apoptosis
Breast Neoplasms
Cell Line
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Fas Ligand Protein
Caspase 9
JNK Mitogen-Activated Protein Kinases
Ionizing radiation
Ionizing Radiation
Tumor Suppressor Genes
Antineoplastic Agents
Modulators
Neoplasms
Genes
Chemical activation
Mutation

ASJC Scopus subject areas

  • Biochemistry

Cite this

BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines. / Thangaraju, Muthusamy; Kaufmann, Scott H.; Couch, Fergus J.

In: Journal of Biological Chemistry, Vol. 275, No. 43, 27.10.2000, p. 33487-33496.

Research output: Contribution to journalArticle

Thangaraju, Muthusamy ; Kaufmann, Scott H. ; Couch, Fergus J. / BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 43. pp. 33487-33496.
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