Is There an Epigenetic Component Underlying the Resistance of Triple-Negative Breast Cancers to Parp Inhibitors?

Abstract

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.

Inhibition of zygotic DNA repair: transcriptome analysis of the offspring in trout (Oncorhynchus mykiss)

“…Tumor cells lacking functional HR system are forced to use the NHEJ pathway, accumulating genetic errors that promote cell death (Lovato et al 2012, Hilton et al 2013, Metzger et al 2013. In our study, the use of 3AB immediately after fertilization was expected to generate an intense genetic stress, considering that first cell cycle lacking the G1-S checkpoint is able to arrest replication (Shimura et al 2002) and then embryos will progress with cleavage.…”

“…One of the signaling enzymes upstream the BER pathway is the poly(ADPribose) polymerase (PARP), catalyzing the so-called 'PARylation', the post-translational addition of ADPribose chains to a wide range of substrates, including the same PARP. Its role in DNA signaling and repair is well known and its inhibition generates an increase in double-strand breaks, leading to genetic instability (Beneke 2012, Lovato et al 2012, Metzger et al 2013. PARP activity has also been strongly suggested in dsDNA repair in the zygote (Matsuda & Tobari 1989).…”

“…PARP activity has also been strongly suggested in dsDNA repair in the zygote (Matsuda & Tobari 1989). PARP inhibition is currently being used to promote cytotoxicity (Lovato et al 2012, Hilton et al 2013) being 3-aminobenzamide (3AB) one of the classical inhibitors.…”

Non-canonical functions of the MDM2 oncoprotein

“…can PARylate itself or other target proteins and this has been shown to be critical in multiple pathways, such as DNA repair, DNA replication, transcription, and cell death (Lovato et al, 2012). The first indication that PARP1 can regulate fork speed came from studies using chemical inhibitors, which have been investigated as therapeutic agents against cancer.…”