Members of the poly (ADP-ribose) polymerase (PARP) family of enzyme proteins are involved in a number of cellular processes such as DNA repair, genomic stability, cell cycle progression, and apoptosis.1,2
- A primary role of PARP1 is to detect single-strand DNA breaks (SSBs) and promote one of the mechanisms for DNA repair, base excision repair (BER).3
- PARP also plays a role in modulating the repair of double strand breaks (DSBs) and is active as a dimer.4,5
- PARP-1 and PARP-2 activity has also been implicated in regulating gene expression through effects on chromatin architecture, DNA metabolism, transcriptional activator and coactivator functions, and maintaining DNA methylation patterns.2,5,6
IMPLICATIONS IN CANCER
PARP inhibitors are thought to exert their antitumor activity by7:
- Inhibiting the catalytic activity of PARP-1 and PARP-2
- Trapping PARP-1 and PARP-2 on damaged DNA and preventing DNA repair, replication, and transcription, leading to replication fork collapse
Inhibition of PARP-1 and -2 may lead to accumulation of single- and double-strand DNA breaks and therefore increased apoptosis in:
- Tumor cells that are exposed to DNA-damaging agents8
- PARP inhibitors may potentiate the effectiveness of chemotherapy or radiation therapy8
- Tumor cells that are deficient in one or more of the DNA repair mechanisms such as homologous recombination (synthetic lethality).1,7
- Inhibition of PARP-1/2 is synthetically lethal with the loss of function of either the BRCA1 or BRCA2 tumor suppressor gene.7
HR-DSR is dependent on functional BRCA 1 and 2 pathways. PARP inhibition leads to replication fork collapse at sites of single-strand breaks, resulting in double-strand breaks. In BRCA-deficient breast cancer, the normal HR-DSR pathway is disrupted, leading to accumulation of unrepaired double-strand breaks and cell death.1,4
- Dependence on PARP-mediated repair may contribute to resistance to DNA-damaging chemotherapeutic agents in BRCA-deficient breast cancer.1
Triple negative breast cancer (TNBC) shares many clinical and pathological similarities with BRCA-deficient breast cancer, including dysfunctional DNA repair mechanisms.1
- There is a high frequency of PARP1 overexpression in TNBC, suggesting that PARP1 may play a role in promoting disease progression.9-11
Overexpression and upregulation of PARP1 in breast cancers is associated with a worse prognosis.10
Approximately 50% of high-grade serous ovarian cancers exhibit defects in HR and DNA repair pathways.12,13 Defects have also been detected in nonserous histologies, including clear-cell, endometrioid, and carcinosarcomas.13
- Anders CK, Winer EP, Ford JM, et al. Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res. 2010;16:4702-4710.
- Caiafa P, Guastafierro T, Zampieri M. Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns. FASEB J. 2009;23(3):672-678.
- Dantzer F, de La Rubia G, Menissier-De Murcia J, et al. Base excision repair is impaired in mammalian cells lacking poly(ADP-ribose) polymerase-1. Biochemistry. 2000;39:7559-7569.
- Audebert M, Salles B, Calsou P. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem. 2004;279(53):55117-55126.
- Lodhi N, Kossenkov AV, Tulin AV. Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark. Nucleic Acids Res. 2014;42(11):7028-7038.
- Ali SO, Khan FA, Galindo-Campos MA, Yélamos J. Understanding specific functions of PARP-2: new lessons for cancer therapy. Am J Cancer Res. 2016;6(9):1842-1863.
- Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-ribose) polymerase. J Pharmacol Exp Ther. 2015;353(3):446-457.
- Plummer ER, Calvert H. Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13:6252-6256.
- Goncalves A, Finetti P, Sabatier R, et al. Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer: a meta-analysis. Breast Cancer Res Treat. 2011;127:273-281.
- Rojo F, Garcia-Parra J, Zazo S, et al. Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol. 2012;23:1156-1164.
- Ossovskaya V, Koo IC, Kaldjian EP, Alvares C, Sherman BM. Upregulation of poly (ADP-Ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer. 2010;1:812-821.
- Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615.
- Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-1154.
- Wysham WZ, Mhawech-Fauceglia P, Li H, et al. BRCAness profile of sporadic ovarian cancer predicts disease recurrence. PLoS One. 2012;7(1):e30042.