Preclinical studies indicate that the inhibition of Poly (ADP-ribose) polymerase-1 (PARP1) can specifically induce cell death of BRCA1- and BRCA2-deficient breast cancer tumor cells owing to the accumulation of unrepairable DNA damage.
Poly (ADP-ribose) polymerase-1 (PARP1) facilitates one of the early DNA-damage signalling responses to DNA single-strand breaks. Preclinical studies indicate that the inhibition of PARP1 can specifically induce cell death of BRCA1- and BRCA2-deficient breast cancer tumour cells owing to the accumulation of unrepairable DNA damage. Consequently, PARP1 inhibitors are currently being evaluated in phase I and II clinical trials. However, Parp1-/- mice have increased mutation rates and an increased incidence of epithelial tumours, including mammary carcinomas, indicating that PARP1 deficiency might independently contribute to the development of cancer.
Tong and colleagues show that Trp53 heterozygous or homozygous mutations in Parp1-/- mice significantly reduce the latency of mammary carcinogenesis that directly results from the loss of Parp1. This is comparable to previous work in mice showing that mammary carcinogenesis resulting from Brca1 or Brca2 mutations is accelerated when Trp53 is also mutated. Furthermore, an examination of mammary tumours derived from Parp1-/-;Trp53-/+ mice showed complete or partial loss of the remaining Trp53 allele, indicating that the loss of p53 and PARP1 is synergistic in the development of mammary carcinoma.
How might the loss of Parp1 affect tumour development? The authors show that Parp1 ablation, particularly when combined with Trp53 homozygous or heterozygous mutations, increases genomic instability and induces centrosome amplification. Interestingly, primary mammary epithelial cells derived from Parp1-/- mice that were treated with doxorubicin to damage DNA showed defective activation of p53 and impaired the recruitment of BRCA1 to DNA double-strand breaks (DSBs). This indicates that PARP1 might also have a role in DSB repair and cell-cycle checkpoint signalling.
Although there is no direct evidence yet that PARP1 mutations are causally associated with human breast tumours, the work by Tong and colleagues raises several issues. First, these observations add weight to indirect evidence that suggests PARP1 mutations or a reduction in PARP1 activity could contribute to carcinogenesis, including that of the breast epithelium. Second, if there is a subset of patients with breast cancer that have defects in PARP1, could the short-term inhibition of factors that mediate DSB repair by homologous recombination, such as CHK1, BRCA1, BRCA2 or RAD51, be therapeutically useful, similar to inhibiting PARP1 in patients with BRCA1- and BRCA2-defective breast cancer? Finally, these observations indicate that prolonged administration of PARP1 inhibitors could be deleterious to cancer patients. Extended, systemic inhibition of PARP1 could not only exacerbate breast cancer development but might increase the risk of developing tumours elsewhere in the body. These and other issues concerning PARP1 inhibitor resistance and the specificity of BRCA1- and BRCA2-deficient tumour cell killing must be addressed in the current and future clinical trials.
Gemma Alderton
References
Tong, W. M. et al. Poly (ADP-ribose) polymerase-1 plays a role in suppressing mammary tumorigenesis in mice. Oncogene (2006) | Article |
Jagtap, P. & Szabo, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nature Rev. Drug Discov.4, 421–440 (2005) | Article | PubMed |
