New research suggests that partial inhibition of poly(ADP-ribose) polymerase-1 (PARP1) may be a safe and effective breast cancer therapy.
According to the US National Cancer Institute (NCI), more than 192,000 American women develop breast cancer each year, with between 5 and 10 per cent of these having a hereditary form of the disease. Inherited mutations in the breast tumour associated genes, BRCA1 and BRCA2 are involved in many of these cases.
Mutations in the BRCA2 gene have also been associated with lymphoma, melanoma, and cancers of the pancreas, gallbladder, bile duct, and stomach in both men and women.
The NCI estimates that lifetime risk of women developing breast cancer are 13.2 per cent for women with no mutations in the BRCA1 and BRCA2 genes, compared with a risk of between 36 and 85 per cent for those who have inherited a mutated gene.
The BRCA1 and BRCA2 genes are involved in the repair of chromosomal damage and are known as tumour suppressor genes that regulate the cycle of cell division. The proteins synthesised by both of these genes are essential for repairing damaged DNA.
Both the BRCA1 gene and the HER-2/neu oncogene are located in close proximity on the long arm of chromosome 17. HER-2 is a target for various therapies, most notably Roche and Genentech's blockbuster monoclonal antibody Herceptin (trastuzumab) which had combined worldwide sales of CHF 2.8bn (€1.7bn) in the first nine months of 2006.
HER-2 overexpression leads to rapid cell growth, and the combination of HER-2 overexpression and mutations of the BRCA1 histologically aggressive, hormone receptor-negative, and highly proliferative breast cancers.
Recent investigations have suggested that the inhibition of another tumour suppressor gene, PARP1 represent a chemopreventive / therapeutic approach for specifically treating BRCA1 and BRCA2 associated breast cancers. This approach selectively kills precancerous BRCA1 deficient cells with high specificity
However, recent research has shown that PARP1-null mutations in mice bearing BRCA1 and BRCA2 mutations lead to genetic instability and mammary tumour formation, casting significant doubt on the safety of PARP1 inhibition therapies for breast cancer.
New research published by scientists from the US National Institute of Health (NIH) in the journal 'Cell Death and Differentiation' have shown that the haploid loss of the PARP1 gene, the loss of just one of the two gene copies (the PARP1-/1 mutation), is sufficient to induce cell apoptosis, programmed cell death in mice bred to contain both the BRCA1?11/?11 mutation.
The study revealed extensive genetic interactions between the BRCA1 and PARP1 genes in the repair of damaged DNA, centrosome duplication and telomere maintenance.
Critically, the study also suggests that the partial inhibition of PARP1 in combination with other drugs may serve as an effective chemopreventive and therapeutic approach for BRCA1 associated cancers.