About one in nine women in the Western world develop cancer of the breast and at least 5% of these cases are thought to result from a hereditary predisposition to the disease. Two breast cancer susceptibility (BRCA)genes have been identified and mutations in these genes account for most families with four or more cases of breast cancer diagnosed before the age of 60. Women who inherit loss-of-function mutations in either of these genes have an up to 85% risk of breast cancer by age 70. As well as breast cancer, carriers of mutations in BRCA1 and BRCA2 are at elevated risk of cancer of the ovary, prostate, and pancreas. The genes are thought to be tumor suppressor genes as the wild-type allele of the gene is observed to be lost in tumors of heterozygous carriers. Both BRCA1 and BRCA2 have significant roles in the maintenance of genome integrity via roles in the repair of DNA damage via homologous recombination. The specific DNA repair defect in BRCA-mutant cells provides opportunities for novel therapeutic approaches based on selective inhibition of functionally interacting repair pathways. These may also be applicable to sporadic cancers harbouring DNA repair defects. Progress towards developing these "synthetic lethal" approaches will be discussed. Selected Publications Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC and Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-21. Turner N, Tutt A, and Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer 2004;4:814-9. Lord CJ, Garrett MD and Ashworth A. Targeting the double-strand DNA break repair pathway as a therapeutic strategy. Clin Cancer Res 2006;12:4463-8. Iorns E, Lord CJ, Turner N, and Ashworth A. Utilizing RNA interference to enhance cancer drug development. Nat Rev Drug Disc 2007;6:556-68.
Second AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development-- Sep 17-20, 2007; Atlanta, GA