Targeting DNA repair in breast cancer: a clinical and translational update.
DNA-repair mechanisms play an important role in the maintenance of DNA integrity and protection against DNA damage. Deregulation of these mechanisms is associated with the development of cancer as is seen in breast tumours with mutations in genes like BRCA1 and BRCA2. Recent biologic findings suggest that in tumours in which one DNA repair pathway is deficient, concomitant inhibition of other repair pathways could have potential synergistic activity. Pharmacological inhibition of Poly (ADP-ribose) polymerase (PARP), a key element of the base excision repair pathway, can have synthetic lethality in tumours with deficient homologous recombination. These findings have paved the way for the clinical development of PARP inhibitors in breast tumours especially in patients with germline mutations in the BRCA1 and/or BRCA2, a population known to have deficient homologous recombination. Patients with sporadic breast cancer, especially those with a basal-like profile may also develop cancer which is deficient in DNA repair and may be susceptible to PARP inhibition. In this review we will update the clinical and biological data underlying the development of drugs targeting DNA repair with a focus on breast cancer.
Amir
Eitan
E
Medical Oncology Department, Princess Margaret Hospital, 610 University Avenue, Toronto, Canada.
Seruga
Bostjan
B
Serrano
Rosario
R
Ocana
Alberto
A
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human