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BAF180 Is a Critical Regulator of p21 Induction and a Tumor Suppressor Mutated in Breast Cancer

¹ Institute for Cancer Genetics, ² Department of Pathology and Cell Biology, ³ Columbia Genome Center, ⁴ Department of Medicine, and ⁵ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York; and ⁶ Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan

Requests for reprints: Ramon Parsons, Columbia University ICRC406, 1130 St. Nicholas Avenue, New York, NY 10032. Phone: 212-851-5278; Fax: 212-851-5267; E-mail: rep15{at}columbia.edu.

Key Words: BAF180 • PB1 • p21/WAF1/CIP1 • tumor suppressor • breast cancer

Screening for tumor suppressor genes in breast cancer revealed multiple truncating mutations of PB1, which encodes the BAF180 subunit of the PBAF chromatin remodeling complex. Mutation was associated with loss of heterozygosity of the wild-type allele. BAF180 complementation of BAF180-mutant tumor cells caused G₁ arrest that was dependent on increased expression of the cyclin/cyclin-dependent kinase inhibitor p21/WAF1/CIP1. Endogenous wild-type BAF180 bound to the p21 promoter and was required for proper p21 expression and G₁ arrest after transforming growth factor-β and -radiation treatment. BAF180 thus functions on two tumor suppressor signaling pathways as a physiologic mediator of p21 expression. We conclude that BAF180 suppresses tumorigenesis, at least in part, through its ability to regulate p21. [Cancer Res 2008;68(6):1667–74]

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