1. ¹International Agency for Research on Cancer (IARC), Lyon, France
2. ²National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
3. ³Department of Pathology, Hospital Edouard Herriot, Lyon, France

Correspondence: Dr WM Tong, Pathology Group, International Agency for Research on Cancer (IARC), 150 cours Albert-Thomas, 69008, Lyon, France. E-mail: tong@iarc.fr

⁴Current address: Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Herts EN6 3LD, UK.

⁵Current address: Leibniz Institute for Age Research-Fritz Lipmann Institute e.V., Jena 07745, Germany.

Received 8 August 2006; Revised 15 September 2006; Accepted 23 October 2006; Published online 11 December 2006.

Abstract

The DNA strand break-binding molecule, poly(ADP-ribose) polymerase-1 (PARP-1), plays a role in DNA repair, chromosomal stability, transcription and cell death. Accumulating evidence suggests that dysfunction of PARP-1 contributes to tumorigenesis. Here, we report that PARP-1 deficiency causes mammary carcinoma formation in female mice, and that the introduction of Trp53 mutations accelerates the onset and shortens the latency of mammary tumorigenesis. We show that PARP-1 deficiency results in chromosomal aneuploidy and centrosome amplification, which are substantiated by the inactivation of Trp53 in primary mammary epithelial (PME) cells. In addition, PARP-1 deficiency compromises p53 activation and impairs BRCA1 recruitment to the sites of DNA damage in PME cells. PARP-1 complementation partly rescues the defective DNA damage response mediated by p53 and BRCA1. The present study thus identifies a role of PARP-1 in suppressing mammary tumorigenesis in vivo and suggests that dysfunction of PARP-1 may be a risk factor for breast cancer in humans.