Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice.
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.
Tong
W M
WM
International Agency for Research on Cancer (IARC), Lyon, France. tong@iarc.fr
Yang
Y G
YG
Cao
W H
WH
Galendo
D
D
Frappart
L
L
Shen
Y
Y
Wang
Z Q
ZQ
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002869:Chromosome Aberrations; D005260:Female; D005455:Fluorescent Antibody Technique; D019656:Loss of Heterozygosity; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D019313:BRCA1 Protein; D016159:Tumor Suppressor Protein p53; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases