Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types

Abstract

IntroductionPoly (ADP-ribose) polymerase-1 (PARP1) is a chromatinassociated enzyme with key functions in the regulation of transcription, cell cycle, tumorigenesis, and cellular response to DNA damage. 1 PARP1 is activated by DNA damage and has important roles in DNA base excision repair (BER), functioning as a nick sensor, recruiter, and modulator of key DNA repair molecules.2 Upon activation, PARP1 synthesizes poly (ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD + ) as a substrate and covalently transfers PAR to nuclear proteins, including nucleosomal core histones, topoisomerases I and II, high mobility group (HMG) proteins, and p53. 3 Loss of PARP1 activity can lead to enhanced cancer cell death, following treatment with PARP inhibitors, both as single agents and in combination with DNA-damaging agents. Impairing PARP1-dependent BER can elicit DNA double-strand breaks (DSBs) following collapse of the replication fork, particularly in cells whose homologous recombination (HR)-dependent DSB repair is already defective due to mutations in breast cancer 1 and 2 genes (BRCA1 and BRCA2); these defects are found frequently in familial breast and ovarian cancers and can elicit profound sensitization to PARP inhibitors, resulting in cytotoxic effects. 4,5 Over 80% of BRCA-associated breast cancers are negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). 6,7 These "triple-negative" breast cancers, which comprise 15% to 20% of all breast cancers, 8,9 are among the most aggressive breast cancer subtypes. Importantly, over 60% AbstractPoly (ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair and is implicated in pathways of tumorigenesis. PARP inhibitors have gained recent attention as rationally designed therapeutics for the treatment of several malignancies, particularly those associated with dysfunctional DNA repair pathways, including triple-negative breast cancer (TNBC). We investigated the PARP1 gene expression profile in surgical samples from more than 8,000 primary malignant and normal human tissues. PARP1 expression was found to be significantly increased in several malignant tissues, including those isolated from patients with breast, uterine, lung, ovarian, and skin cancers, and non-Hodgkin's lymphoma. Within breast infiltrating ductal carcinoma (IDC) samples tested, mean PARP1 expression was significantly higher relative to normal breast tissue, with over 30% of IDC samples demonstrating upregulation of PARP1, compared with 2.9% of normal tissues. Because of known DNA repair defects, including BRCA1 dysfunction, associated with TNBC, exploration of PARP1 expression in breast cancers related to expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) led to the observation that negative expression of any of the 3 receptors was associated with upregulation of PARP1 expression, compared with receptor-positive tissues. To validate these observations, an indep...

PARP1 Is Overexpressed in Nasopharyngeal Carcinoma and Its Inhibition Enhances Radiotherapy

“…Several studies have reported the association of PARP1 protein expression with a worse prognosis. For example, PARP1 overexpression is associated with overall poor prognosis, higher tumor grade, BRCA1-mutated and triple-negative phenotype breast cancers (29)(30)(31). In nasopharyngeal carcinoma, PARP1 expression was correlated with increase in patient age and poorer survival (Table 3).…”

Variations in the mRNA expression of poly(ADP‐ribose) polymerases, poly(ADP‐ribose) glycohydrolase and ADP‐ribosylhydrolase 3 in breast tumors and impact on clinical outcome

“…Ossovskaya et al 20 showed a higher incidence of PARP1 upregulation in TNBC tumors compared with receptor positive samples while Goncalves et al 21 observed PARP1 mRNA overexpression in basal breast cancer but also in other subtypes. In our study, PARP1 transcript levels were higher in HR1/ERBB21 tumors compared to other subtypes but as reported by Goncalves et al 21 overexpression of PARP1 compared with normal tissue was observed in all subtypes.…”

“…This PARP1 mRNA profile is in agreement with three smaller studies from the same treatment centre [17][18][19] and several other recent reports. For instance, Ossovskaya et al 20 found that 30% of breast infiltrating ductal carcinoma samples showed an upregulation of PARP1 mRNA compared with 2.9% of the normal tissues examined. A recent metaanalysis 21 performed on 2485 breast cancer tumors in 12 publically available oligonucleotide microarray data sets also found a twofold overexpression of PARP1 mRNA in 58% of tumors.…”

Cisplatin Resistance Associated with PARP Hyperactivation

“…PARP1 and 2 are the most abundant and best-characterized members of this family and are involved in transcriptional regulation, DNA repair, as well as in the maintenance of genomic stability (3)(4)(5). PARP1, which is mostly localized to the nucleus, accounts for approximately 75% of overall PARP enzymatic activity, fixing PAR polymers on multiple nuclear, cytoplasmic, and mitochondrial substrates, including proteins that modulate chromatin structure (e.g., histones, topoisomerases I and II), factors that stimulate DNA synthesis and repair (e.g., XRCC1, DNA polymerases a and b, DNA ligases I and II), and transcriptional regulators (e.g., p53; refs.…”