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Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene1,2,3. The nuclear protein BRCA1 has the

properties of a transcription factor4,5,6,7, and can interact with the recombination and repair protein RAD51 (ref. 8). Young women with germline alterations in BRCA1 develop breast cancer

at rates 100-fold higher than the general population3, and BRCA1-null mice die before day 8 of development9,10. However, the mechanisms of BRCA1-mediated growth regulation and tumour

suppression remain unknown. Here we show that BRCA1 transactivates expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in a p53-independent manner, and that BRCA1 inhibits

cell-cycle progression into the S-phase following its transfection into human cancer cells. BRCA1 does not inhibit S-phase progression in p21−/− cells, unlike p21+/+ cells, and

tumour-associated, transactivation-deficient mutants of BRCA1 are defective in both transactivation of p21 and cell-cycle inhibition. These data suggest that one mechanism by which BRCA1

contributes to cell-cycle arrest and growth suppression is through the induction of p21.

This work was supported by grants from the NIH and the Breast Cancer Research Foundation to B.L.W. W.S.E.-D. is an assistant investigator of the Howard Hughes Medical Institute.

Kumaravel Somasundaram and Hongbing Zhang: These authors contributed equally to this study.

Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

Kumaravel Somasundaram, Yi-Xin Zeng, Gen Sheng Wu & Wafik S. El-Deiry

Departments of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

Kumaravel Somasundaram, Hongbing Zhang, Yi-Xin Zeng, Yi Peng, Hongxiang Zhang, Gen Sheng Wu, Barbara L. Weber & Wafik S. El-Deiry

Departments of Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

Departments of Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

Brookdale Center for Developmental and Molecular Biology and Department of Medicine, The Mount Sinai School of Medicine, New York, 10029, New York, USA

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