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Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice

Oncogene volume 26, pages 3857–3867 (2007)Cite this article

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.

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Acknowledgements

We thank C Granier, L Haddad, YG Xi, A Sadi, C Carreira and N Lyandrat for technical assistance. We are also grateful to Dr CX Deng for BRCA1 antibody (BRCA1-1059). Further thanks are due to Drs G Lenoir, J Hall and B Sedgwick for comments and to J Daniel for editing the manuscript. WM Tong was supported in part by grants from the Comité départemental de la Loire and de la Drôme, la Ligue Nationale Contre le Cancer, France. ZQ Wang was supported by Association pour la Recherche sur le Cancer, France. WH Cao is a predoctoral fellow supported by the International Agency for Research on Cancer (IARC), France.

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Author notes

  1. Y G Yang

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

  2. D Galendo & Z Q Wang

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

Authors and Affiliations

  1. International Agency for Research on Cancer (IARC), Lyon, France

    W M Tong, Y G Yang, W H Cao, D Galendo & Z Q Wang

  2. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    W H Cao & Y Shen

  3. Department of Pathology, Hospital Edouard Herriot, Lyon, France

    L Frappart

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Correspondence to W M Tong.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Tong, W., Yang, Y., Cao, W. et al. Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice. Oncogene 26, 3857–3867 (2007). https://doi.org/10.1038/sj.onc.1210156

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