Is there an epigenetic component underlying the resistance of triple-negative breast cancers to Parp inhibitors?
- The Departments of Oncology and Experimental Medicine, The Lady Davis Institute and Segal Cancer Centre of the Jewish General Hospital, McGill University Montreal, QC, Canada
Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on in vitro and clinical studies it remains unclear to what extent Parp inhibitors can be utilized beyond treating Brca mutated tumors. This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.
Keywords: Parp inhibitors, epigenetics, breast cancer, transcription factors, therapeutic resistance
Citation: Lovato A, Panasci L and Witcher M (2012) Is there an epigenetic component underlying the resistance of triple-negative breast cancers to Parp inhibitors? Front. Pharmacol. 3:202. doi: 10.3389/fphar.2012.00202
Received: 11 October 2012; Paper pending published: 01 November 2012;
Accepted: 06 December 2012; Published online: 27 December 2012.
Copyright: © 2012 Lovato, Panasci and Witcher. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Michael Witcher, The Department of Oncology, The Lady Davis Institute and Segal Cancer Centre of the Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2. e-mail: email@example.com