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Tumor Biology
Published in: Tumor Biology 5/2016

01-05-2016 | Original Article

Nuclear PARP1 expression and its prognostic significance in breast cancer patients

Authors: Annalisa Mazzotta, Giulia Partipilo, Simona De Summa, Francesco Giotta, Giovanni Simone, Anita Mangia

Published in: Tumor Biology | Issue 5/2016

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Abstract

Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) plays important roles in DNA damage response pathways and is often overexpressed in various human tumors. Currently, the use of PARP inhibitors for breast cancer (BC) therapy is the subject of debate, and there is an urgent need to understand much the expression and prognostic role of the PARP1 protein. The aim was to investigate the clinicopathological and prognostic significance of PARP1 in BC patients. The PARP1 and breast cancer susceptibility gene 1 (BRCA1) protein expressions were evaluated in 114 BCs by immunohistochemistry. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Our results showed that nuclear PARP1 expression was significantly associated with peritumoral vascular invasion (P = 0.046), chemotherapeutic treatment (P = 0.026), oestrogen receptor (ER; P = 0.013), human epidermal growth factor receptor 2 (HER2; P = 0.003) and BRCA1 (P < 0.001) expression. Survival analyses showed a significant association with clinical outcome in the subgroup of ER-negative patients (P = 0.017 for DFS and P = 0.048 for OS) and in the subgroup of patients treated with chemotherapeutic agents (P = 0.042 for DFS and P = 0.046 for OS). A significant correlation was also found for DFS in patients characterized by tumors without peritumoral vascular invasion (P = 0.022). More importantly, multivariate analyses revealed that high nuclear PARP1 expression was associated with decreased DFS (P = 0.012) and OS (P = 0.026). In conclusion, PARP1 expression may be used as an independent prognostic factor in BC patients. In addition, this study demonstrated that high PARP1 expression may represent a marker of poorer prognosis both for patients with worse clinical outcome and in less aggressive clinical conditions.
Literature
1.
Bray F, Ren JS, Masuyer E, Ferlay J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013;132:1133–45.CrossRefPubMed
2.
3.
Schnitt SJ. Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy. Mod Pathol. 2010;23:S60–4.CrossRefPubMed
4.
Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006;7:517–28.CrossRefPubMed
5.
Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13:411–24.CrossRefPubMed
6.
Dantzer F, de La Rubia G, Ménissier-De Murcia J, Hostomsky Z, de Murcia G, Schreiber V. Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1. Biochemistry. 2000;39:7559–69.CrossRefPubMed
7.
8.
Tutt A, Ashworth A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med. 2002;8:571–6.CrossRefPubMed
9.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34.CrossRefPubMed
10.
Burstein HJ. Novel agents and future directions for refractory breast cancer. Semin Oncol. 2011;38:S17–24.CrossRefPubMed
11.
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–7.CrossRefPubMed
12.
13.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.CrossRefPubMed
14.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235–44.CrossRefPubMed
15.
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92.CrossRefPubMed
16.
Sonnenblick A, de Azambuja E, Azim Jr HA, Piccart M. An update on PARP inhibitors--moving to the adjuvant setting. Nat Rev Clin Oncol. 2015;12:27–41.CrossRefPubMed
17.
Liang H, Tan AR. Iniparib, a PARP1 inhibitor for the potential treatment of cancer, including triple-negative breast cancer. IDrugs. 2010;13:646–56.PubMed
18.
O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205–14.CrossRefPubMed
19.
Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14:882–92.CrossRefPubMed
20.
O’Sullivan CC, Moon DH, Kohn EC, Lee JM. Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid tumors. Front Oncol. 2014;4:42.PubMedPubMedCentral
21.
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244–50.CrossRefPubMed
22.
McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66:8109–15.CrossRefPubMed
23.
24.
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852–61.CrossRefPubMed
25.
Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH. Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clin Cancer Res. 2012;18:1655–62.CrossRefPubMedPubMedCentral
26.
Barber LJ, Sandhu S, Chen L, Campbell J, Kozarewa I, Fenwick K, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol. 2013;229:422–9.CrossRefPubMed
27.
Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013;3:68–81.CrossRefPubMed
28.
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;1:812–21.CrossRefPubMedPubMedCentral
29.
Quiles-Perez R, Muñoz-Gámez JA, Ruiz-Extremera A, O’Valle F, Sanjuán-Nuñez L, Martín-Alvarez AB, et al. Inhibition of poly adenosine diphosphate-ribose polymerase decreases hepatocellular carcinoma growth by modulation of tumor-related gene expression. Hepatology. 2010;51:255–66.CrossRefPubMed
30.
Salemi M, Galia A, Fraggetta F, La Corte C, Pepe P, La Vignera S, et al. Poly (ADP-ribose) polymerase 1 protein expression in normal and neoplastic prostatic tissue. Eur J Histochem. 2013;57:e13.CrossRefPubMedPubMedCentral
31.
von Minckwitz G, Müller BM, Loibl S, Budczies J, Hanusch C, Darb-Esfahani S, et al. Cytoplasmic poly(adenosine diphosphate-ribose) polymerase expression is predictive and prognostic in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol. 2011;29:2150–7.CrossRef
32.
Rojo F, García-Parra J, Zazo S, Tusquets I, Ferrer-Lozano J, Menendez S, et al. Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol. 2012;23:1156–64.CrossRefPubMed
33.
Donizy P, Pietrzyk G, Halon A, Kozyra C, Gansukh T, Lage H, et al. Nuclear-cytoplasmic PARP-1 expression as an unfavorable prognostic marker in lymph node-negative early breast cancer: 15-year follow-up. Oncol Rep. 2014;31:1777–87.PubMed
34.
Park SH, Noh SJ, Kim KM, Bae JS, Kwon KS, Jung SH, et al. Expression of DNA damage response molecules PARP1, γH2AX, BRCA1, and BRCA2 predicts poor survival of breast carcinoma patients. Transl Oncol. 2015;8:239–49.CrossRefPubMedPubMedCentral
35.
Green AR, Caracappa D, Benhasouna AA, Alshareeda A, Nolan CC, Macmillan RD, et al. Biological and clinical significance of PARP1 protein expression in breast cancer. Breast Cancer Res Treat. 2015;149:353–62.CrossRefPubMed
36.
Aleskandarany M, Caracappa D, Nolan CC, Macmillan RD, Ellis IO, Rakha EA, et al. DNA damage response markers are differentially expressed in BRCA-mutated breast cancers. Breast Cancer Res Treat. 2015;150:81–90.CrossRefPubMedPubMedCentral
37.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403–10.CrossRefPubMed
38.
Domagala P, Huzarski T, Lubinski J, Gugala K, Domagala W. PARP-1 expression in breast cancer including BRCA1-associated, triple negative and basal-like tumors: possible implications for PARP-1 inhibitor therapy. Breast Cancer Res Treat. 2011;127:861–9.CrossRefPubMed
39.
Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies-improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer 2015. Ann Oncol. 2015;26:1533–46.CrossRefPubMedPubMedCentral
40.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Pathol Lab Med. 2007;131:18–43.
41.
42.
Domagala P, Lubinski J, Domagala W. Iniparib in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:1780. author reply 1781.CrossRefPubMed
43.
Ozretić L, Rhiem K, Huss S, Wappenschmidt B, Markiefka B, Sinn P, et al. High nuclear poly(adenosine diphosphate-ribose) polymerase expression is predictive for BRCA1- and BRCA2-deficient breast cancer. J Clin Oncol. 2011;29:4586–8. author reply 4588.CrossRefPubMed
44.
Kim MY, Mauro S, Gévry N, Lis JT, Kraus WL. NAD+−dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1. Cell. 2004;119:803–14.CrossRefPubMed
45.
Zhang F, Wang Y, Wang L, Luo X, Huang K, Wang C, et al. Poly(ADP-ribose) polymerase 1 is a key regulator of estrogen receptor α-dependent gene transcription. J Biol Chem. 2013;288:11348–57.CrossRefPubMedPubMedCentral
46.
Stanley J, Klepczyk L, Keene K, Wei S, Li Y, Forero A, et al. PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers. Breast Cancer Res Treat. 2015;150:569–79.CrossRefPubMedPubMedCentral
47.
Nowsheen S, Cooper T, Bonner JA, LoBuglio AF, Yang ES. HER2 overexpression renders human breast cancers sensitive to PARP inhibition independently of any defect in homologous recombination DNA repair. Cancer Res. 2012;72:4796–806.CrossRefPubMedPubMedCentral
48.
Partipilo G, Simone G, Scattone A, Scarpi E, Azzariti A, Mangia A. Expression of proteins involved in DNA damage response in familial and sporadic breast cancer patients. Int J Cancer. 2015.
49.
Wysham WZ, Mhawech-Fauceglia P, Li H, Hays L, Syriac S, Skrepnik T, et al. BRCAness profile of sporadic ovarian cancer predicts disease recurrence. PLoS One. 2012;7:e30042.CrossRefPubMedPubMedCentral
50.
Hu Y, Petit SA, Ficarro SB, Toomire KJ, Xie A, Lim E, et al. PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov. 2014;4:1430–47.CrossRefPubMedPubMedCentral
51.
Li D, Bi FF, Chen NN, Cao JM, Sun WP, Zhou YM, et al. A novel crosstalk between BRCA1 and poly (ADP-ribose) polymerase 1 in breast cancer. Cell Cycle. 2014;13:3442–9.CrossRefPubMedPubMedCentral
Metadata
Title
Nuclear PARP1 expression and its prognostic significance in breast cancer patients
Authors
Annalisa Mazzotta
Giulia Partipilo
Simona De Summa
Francesco Giotta
Giovanni Simone
Anita Mangia
Publication date
01-05-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 5/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4465-0

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