Targeting PARP1 in Breast Cancer: The Paradigm of a DNA repair-based Therapeutic Strategy

Abstract

Poly(ADP-ribose) polymerases (PARPs) are defined as cell signalling enzymes that catalyze the transfer of ADP-ribose units from NAD(+) to a number of acceptor proteins. PARP-1, the best characterized member of the PARP family, that presently includes eighteen members, is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress. PARP is involved in DNA repair and transcriptional regulation, and is now recognized as a key regulator of cell survival and cell death as well as a master component of a number of transcription factors involved in tumor development and inflammation. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionizing radiation and DNA damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA) 1 and 2 genes and other 286mutations affecting the cell’s efficiency to cope with homologous recombination. The aim of the present chapter is to overview the emerging data in the literature on the mechanistic insights of poly(ADP-ribose) polymerase-1 (PARP-1) in the pathway of homologous recombination and the consequences for the therapeutic intervention in familiar and refractory breast cancer. PARP, poly(ADP-ribose), BRCA1/2, DNA repair, homologous recombination, angiogenesis, anticancer therapy, breast cancer.