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RAD51 Up-regulation Bypasses BRCA1 Function and Is a Common Feature of BRCA1-Deficient Breast Tumors

Departments of ¹ Radiation and Cellular Oncology and ² Molecular Genetics and Cell Biology and ³ Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois, and ⁴ Radiation Genetics, Faculty of Medicine, Kyoto University, CREST Research Project, Japan Science and Technology, Kyoto, Japan

Requests for reprints: Douglas K. Bishop, Cummings Life Science Center, Box 13, Room 821, 920 East 58th Street, Chicago, IL 60637. Phone: 773-702-9211; Fax: 773-834-9064; E-mail: dbishop{at}uchicago.edu.

The breast cancer susceptibility gene BRCA1 encodes a large protein thought to contribute to a variety of cellular processes, although the critical determinants of BRCA1-deficient tumorigenesis remain unclear. Given that BRCA1 is required for cell proliferation, suppressor mutations are believed to modify BRCA1 phenotypes and contribute to the etiology of BRCA1-deficient tumors. Here, we show that overexpression of the homologous recombinase RAD51 in a DT40 BRCA1^/ mutant rescues defects in proliferation, DNA damage survival, and homologous recombination (HR). In addition, epistasis analysis with BRCA1 and the DNA end-joining factor KU70 indicates that these factors operate independently of one another to repair double-strand breaks. Consistent with this genetic finding, cell synchronization studies show that the ability of BRCA1 to promote radioresistance is restricted to the late S and G₂ phases of the cell cycle, as predicted for genes whose function is specific to homology-mediated repair rather than nonhomologous end-joining. Notably, retrospective analyses of microarray expression data reveal elevated expression of RAD51 and two of its late-acting cofactors, RAD54 and RAD51AP1, in BRCA1-deficient versus sporadic breast tumors. Taken together, our results indicate that up-regulation of HR provides a permissive genetic context for cells lacking BRCA1 function by circumventing its requirement in RAD51 subnuclear assembly. Furthermore, the data support a model in which enhanced HR activity contributes to the etiology of BRCA1-deficient tumors. [Cancer Res 2007;67(20):9658–65]

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