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RESEARCH PAPER

Collaboration of Brca1 and Chk2 in tumorigenesis

¹ Advanced Medical Discovery Institute, Ontario Cancer Institute, Toronto, Ontario M5G 2C1, Canada; ² Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; ³ The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, Shinjuku, Tokyo 160-8582, Japan; ⁴ Department of Physiology, Faculty of Medicine, National University of Singapore, 117597 Singapore

Disruption of Brca1 results in cellular demise or tumorigenesis depending on cellular context. Inactivation of p53 contributes to Brca1-associated tumor susceptibility. However the activation of p53-dependent checkpoint/apoptotic signaling in the absence of Brca1 is poorly understood. Here, we show that Chk2 inactivation is partially equivalent to p53 inactivation, in that Chk2 deficiency facilitates the development, survival, and proliferation of Brca1-deficient T cells at the expense of genomic integrity. Brca1 deficiency was found to result in Chk2 phosphorylation and the Chk2-dependent accumulation and activation of p53. Furthermore, inactivation of Chk2 and Brca1 was cooperative in breast cancer. Our findings identify a critical role for Chk2 as a component of the DNA damage-signaling pathway activated in response to Brca1 deficiency.

[Keywords: Breast cancer; T cell; genomic instability; apoptosis; cell cycle; proliferation]

Received February 10, 2004; revised version accepted April 2, 2004.

Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1192704.

⁵ Present address: Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

⁶ These authors contributed equally to this work.

⁷ Corresponding author.

E-MAIL rhakem{at}uhnres.utoronto.ca; FAX (416) 204-2277.

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