Because dysregulation of PARP expression might lead to genetic instability in human tumors, we examined PARP gene expression and genetic instability in 35 primary human breast carcinomas.
The importance of a genetic polymorphism (A/B allele) of poly(ADP-ribose) polymerase (PARP) pseudogene on chromosome 13q34-qter, and PARP enzyme activities in the development of human breast cancer were evaluated in a cancer case-control study.
The purpose of the present study was to investigate the reversal mechanism of doxo resistance by the potent PARP [poly(ADP-ribose) polymerase] inhibitor ANI (4-amino-1,8-naphthalimide) in the p53-deficient breast cancer cell lines EVSA-T and MDA-MB-231.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces oxidative stress, DNA strand breaks, and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines.
We have conducted here an exhaustive detailed mutation and haplotype tagging analysis of the ADPRT gene with regard to breast cancer, providing useful data for other large-scale association studies.
The present study implies that genetic variants of PARP-1 may contribute to breast cancerogenesis and that PARP-1 htSNP c.852T>C (Ala284Ala) may influence hormonal therapy of breast cancer.
However, there were significant trends in breast cancer risk with increasing numbers of risk genotypes for ADPRT 762VV, APE1 148DD, ERCC4 415RQ/QQ and MLH1 219II/IV (P(trend) < 0.001) in Caucasians and ADPRT 762VA, ERCC2 751KQ/QQ and NBS1 185EQ/QQ in African-Americans (P(trend) = 0.006), respectively.
Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA) 1 and 2 genes.
This method may, therefore, serve as a marker for breast cancer risk assessment and, even more importantly, for the prediction of responsiveness to targeted therapies such as to inhibitors of poly(ADP-ribose)polymerase (PARP1).
Using this approach we have previously demonstrated that inhibition of the DNA repair protein, PARP1, is synthetically lethal with deficiency of either of the breast cancer susceptibility proteins, BRCA1 and BRCA2.
These results suggest a potential broader utility of PARP-1 inhibitors in the treatment of breast cancer, although further mechanistic studies are needed.
Why PARP inhibitors are synthetically lethal to certain tumours and the specific role this class of drugs may play in the treatment of breast cancer is reviewed.
Inhibition of PARP-1 exerts "synthetic lethality" effect towards the tumors with defects in DNA repair by homologous recombination, specifically the tumors with mutations in the breast cancer associated BRCA1 and BRCA2 genes.
Without adjustment for multiple testing, multivariate analysis demonstrated an association with increased bladder cancer risk with PARP1rs8679 (P(trend) = 0.05) while variant homozygotes of PARP1rs8679 were also noted to have an increased breast cancer risk (P = 0.03).