Hereditary Breast and Ovarian Cancer and Poly(ADP-ribose) Polymerase Inhibition

Hereditary breast and ovarian cancer (HBOC) is a syndrome due to heterozygous germ line mutations in one of several genes. Of particular interest are the genes involved in homologous recombination, BRCA1, BRCA2, and PALB2. Germ line mutations in these genes lead to breast, ovarian, prostate, and pancreatic cancers with defects in homologous recombination due to loss of heterozygosity. Poly(ADP-ribose) polymerase 1 (PARP-1) inhibition blocks the repair of DNA single-strand breaks by DNA polymerase beta. The advancing replication fork converts the unrepaired singlestrand breaks to double-strand breaks, which can be lethal for a cancer cell that is defective in homologous recombination. Thus, PARP-1 inhibitors show great promise in the treatment of cancers with mutations in BRCA1, BRCA2, or PALB2.