Open Access Peer-reviewed

Clinical and Molecular Significance of Poly (ADP-Ribose) Polymerase-1 (PARP-1) in Breast Cancer of African Women and its Potential as a Targeted Therapy

Ayodeji O.J Agboola1, 2,, Adekunbiola A. F Banjo2, Charles C Anunobi2, Babatunde A Ayoade3, Mopelola A Deji Agboola4, Adewale. A Musa3, Christopher C Nolan1, Emad A. Rakha1, Andrew R. Green1, Ian O. Ellis1

1Division of Pathology, School of Molecular Medical Sciences, Nottingham University Hospitals and University of Nottingham, Nottingham, United Kingdom

2Department of Morbid Anatomy and Histopathology, Olabisi Onabanjo University and Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria

3Department of Surgery, Olabisi Onabanjo University and Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria

4Department of Medical Microbiology parasitology, Olabisi Onabanjo University, Sagamu, Nigeria

Journal of Cancer Research and Treatment. 2013, 1(2), 24-30. DOI: 10.12691/jcrt-1-2-1
Published online: August 25, 2017

Abstract

Background: The therapeutic effects of Poly (ADP-ribose) polymerase-1 (PARP -1) inhibition are currently studied in a clinical trial that is recruiting African- American (A-A) women with breast cancer (BC). Although, A-A and West African women are likely to share the same ancestry, there are overwhelming evidences, that BC is undoubtedly heterogeneous which might influence results obtained in these Nationalities. Thus, this study aims to investigate PARP-1 expression in a large and annotated series of breast cancer from Nigerian women to determine its clinical and biological significance for the indigenous African women. Methods: PARP-1 protein expression was assessed immunohistochemically in 204 formalin fixed paraffin samples from Nigerian breast cancer women prepared as TMA. Results: PARP-1 was inversely associated with steroid hormone receptors (oestrogen (ER) and progesterone (PR) receptor), the Homologous Recombination marker BRCA1 associated ring domain 1 (BARD1) and p27. Conversely, a positive association was established between PARP-1 and high histologic grade, expression of basal markers (cytokeratins (CK) 5/6 and 14) and epidermal growth factor receptor (EGFR)), DNA damage-repair markers (protein inhibitor of activator signal transducer gamma (PIAS)), the BRCA1 inhibitor (metastasis tumour antigen-1 (MTA1), p53, the proliferation markers (KI-67, Phosphoinositide-3-kinases (PI3KCA)), the triple-negative and basal-like phenotypes. Outcome analysis indicated PARP-1 as a predictor of poor survival independent of tumour size, histological grade and lymph node involvement. Conclusion: These results provide evidence that PARP-1 plays an important role in Nigerian women with breast cancer. It is recommended that indigenous Black women from Africa are included in the ongoing clinical trial of PARP1 inhibitors that is aimed at determining the efficiency of the drug in black BC women outside United States.

Keywords:

PARP-1, African women, therapeutics potential, breast cancer
[1]  Kim MY, Zhang T, Kraus WL: Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. Genes & development 2005, 19(17):1951-1967.View Article  PubMed
 
[2]  Kraus WL: Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Current opinion in cell biology 2008, 20(3):294-302.View Article  PubMed
 
[3]  De Vos M, Schreiber V, Dantzer F: The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochemical pharmacology 2012, 84(2):137-146.View Article  PubMed
 
[4]  Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, Durkacz BW, Hostomsky Z, Kumpf RA, Kyle S et al: Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. Journal of the National Cancer Institute 2004, 96(1):56-67.View Article  PubMed
 
[5]  Chalmers AJ, Lakshman M, Chan N, Bristow RG: Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. Seminars in radiation oncology 2010, 20(4):274-281.View Article  PubMed
 
[6]  Powell C, Mikropoulos C, Kaye SB, Nutting CM, Bhide SA, Newbold K, Harrington KJ: Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers. Cancer treatment reviews 2010, 36(7):566-575.View Article  PubMed
 
[7]  Munoz-Gamez JA, Martin-Oliva D, Aguilar-Quesada R, Canuelo A, Nunez MI, Valenzuela MT, Ruiz de Almodovar JM, De Murcia G, Oliver FJ: PARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis. The Biochemical journal 2005, 386(Pt 1):119-125. PubMed
 
[8]  Csete B, Lengyel Z, Kadar Z, Battyani Z: Poly(adenosine diphosphate-ribose) polymerase-1 expression in cutaneous malignant melanomas as a new molecular marker of aggressive tumor. Pathology oncology research : POR 2009, 15(1):47-53. PubMed
 
[9]  Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434(7035):913-917.View Article  PubMed
 
[10]  Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ et al: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England journal of medicine 2009, 361(2):123-134.View Article  PubMed
 
[11]  Agboola AO, Banjo AA, Anunobi CC, Salami B, Agboola MD, Musa AA, Nolan CC, Rakha EA, Ellis IO, Green AR: Cell Proliferation (KI-67) Expression Is Associated with Poorer Prognosis in Nigerian Compared to British Breast Cancer Women. ISRN oncology 2013, 2013:675051.
 
[12]  Agboola AJ, Musa AA, Wanangwa N, Abdel-Fatah T, Nolan CC, Ayoade BA, Oyebadejo TY, Banjo AA, Deji-Agboola AM, Rakha EA et al: Molecular characteristics and prognostic features of breast cancer in Nigerian compared with UK women. Breast cancer research and treatment 2012, 135(2):555-569.View Article  PubMed
 
[13]  Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007, 25(1):118-145.View Article  PubMed
 
[14]  Garcia-Caballero T, Grabau D, Green AR, Gregory J, Schad A, Kohlwes E, Ellis IO, Watts S, Mollerup J: Determination of HER2 amplification in primary breast cancer using dual-colour chromogenic in situ hybridization is comparable to fluorescence in situ hybridization: a European multicentre study involving 168 specimens. Histopathology, 56(4):472-480.View Article  PubMed
 
[15]  Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L et al: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 2004, 10(16):5367-5374.
 
[16]  McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM: Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 2005, 23(36):9067-9072.View Article  PubMed
 
[17]  Agboola AJ, Musa AA, Wanangwa N, Abdel-Fatah T, Nolan CC, Ayoade BA, Oyebadejo TY, Banjo AA, Deji-Agboola AM, Rakha EA et al: Molecular characteristics and prognostic features of breast cancer in Nigerian compared with UK women. Breast cancer research and treatment 2012.View Article
 
[18]  Gao R, Price DK, Sissung T, Reed E, Figg WD: Ethnic disparities in Americans of European descent versus Americans of African descent related to polymorphic ERCC1, ERCC2, XRCC1, and PARP1. Molecular cancer therapeutics 2008, 7(5):1246-1250.View Article  PubMed
 
[19]  Gu J, Spitz MR, Yang F, Wu X: Ethnic differences in poly(ADP-ribose) polymerase pseudogene genotype distribution and association with lung cancer risk. Carcinogenesis 1999, 20(8):1465-1469.View Article  PubMed
 
[20]  Shiao YH, Chen VW, Scheer WD, Wu XC, Correa P: Racial disparity in the association of p53 gene alterations with breast cancer survival. Cancer Res 1995, 55(7):1485-1490. PubMed
 
[21]  Gao Q, Tomlinson G, Das S, Cummings S, Sveen L, Fackenthal J, Schumm P, Olopade OI: Prevalence of BRCA1 and BRCA2 mutations among clinic-based African American families with breast cancer. Hum Genet 2000, 107(2):186-191.View Article  PubMed
 
[22]  John EM, Miron A, Gong G, Phipps AI, Felberg A, Li FP, West DW, Whittemore AS: Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA : the journal of the American Medical Association 2007, 298(24):2869-2876.View Article  PubMed
 
[23]  Fackenthal JD, Sveen L, Gao Q, Kohlmeir EK, Adebamowo C, Ogundiran TO, Adenipekun AA, Oyesegun R, Campbell O, Rotimi C et al: Complete allelic analysis of BRCA1 and BRCA2 variants in young Nigerian breast cancer patients. J Med Genet 2005, 42(3):276-281.View Article  PubMed
 
[24]  Olopade OI, Fackenthal JD, Dunston G, Tainsky MA, Collins F, Whitfield-Broome C: Breast cancer genetics in African Americans. Cancer 2003, 97(1 Suppl):236-245.View Article  PubMed
 
[25]  Grabsch H, Dattani M, Barker L, Maughan N, Maude K, Hansen O, Gabbert HE, Quirke P, Mueller W: Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2006, 12(5):1494-1500.
 
[26]  Verlinden L, Vanden Bempt I, Eelen G, Drijkoningen M, Verlinden I, Marchal K, De Wolf-Peeters C, Christiaens MR, Michiels L, Bouillon R et al: The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor /progesterone receptor /HER-2 breast carcinomas. Cancer research 2007, 67(14):6574-6581.View Article  PubMed
 
[27]  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 research and treatment 2011, 127(3):861-869.View Article  PubMed
 
[28]  Maacke H, Opitz S, Jost K, Hamdorf W, Henning W, Kruger S, Feller AC, Lopens A, Diedrich K, Schwinger E et al: Over-expression of wild-type Rad51 correlates with histological grading of invasive ductal breast cancer. International journal of cancer Journal international du cancer 2000, 88(6):907-913.
 
[29]  Lindahl T: Instability and decay of the primary structure of DNA. Nature 1993, 362(6422):709-715.View Article  PubMed
 
[30]  D'Amours D, Desnoyers S, D'Silva I, Poirier GG: Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. The Biochemical journal 1999, 342 ( Pt 2):249-268.View Article  PubMed
 
[31]  Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP: The role of BRCA1 in the cellular response to chemotherapy. Journal of the National Cancer Institute 2004, 96(22):1659-1668.View Article  PubMed
 
[32]  Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, Ried T, Nussenzweig A: DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 2000, 404(6777):510-514.View Article  PubMed
 
[33]  Luo X, Kraus WL: On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes & development 2012, 26(5):417-432.View Article  PubMed
 
[34]  Tong WM, Yang YG, Cao WH, Galendo D, Frappart L, Shen Y, Wang ZQ: Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice. Oncogene 2007, 26(26):3857-3867.View Article  PubMed
 
[35]  Cheng GH, Wu N, Jiang DF, Zhao HG, Zhang Q, Wang JF, Gong SL: Increased levels of p53 and PARP-1 in EL-4 cells probably related with the immune adaptive response induced by low dose ionizing radiation in vitro. Biomedical and environmental sciences : BES 2010, 23(6):487-495. PubMed
 
[36]  Inbar-Rozensal D, Castiel A, Visochek L, Castel D, Dantzer F, Izraeli S, Cohen-Armon M: A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors. Breast cancer research : BCR 2009, 11(6):R78.View Article  PubMed
 
[37]  Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP: Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 2009, 462(7275):935-939.View Article  PubMed
 
[38]  Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, Hiddingh S, Thanasoula M, Kulkarni A, Yang Q et al: 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nature structural & molecular biology 2010, 17(6):688-695.View Article  PubMed
 
[39]  Morris JR, Boutell C, Keppler M, Densham R, Weekes D, Alamshah A, Butler L, Galanty Y, Pangon L, Kiuchi T et al: The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 2009, 462(7275):886-890.View Article  PubMed
 
[40]  Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP: MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 2005, 123(7):1213-1226.View Article  PubMed
 
[41]  Ryu H, Al-Ani G, Deckert K, Kirkpatrick D, Gygi SP, Dasso M, Azuma Y: PIASy mediates SUMO-2/3 conjugation of poly(ADP-ribose) polymerase 1 (PARP1) on mitotic chromosomes. The Journal of biological chemistry 2010, 285(19):14415-14423.View Article  PubMed
 
[42]  Tuma RS: PARP inhibitors: will the new class of drugs match the hype? Journal of the National Cancer Institute 2009, 101(18):1230-1232.View Article  PubMed
 
[43]  Cao WH, Wang X, Frappart L, Rigal D, Wang ZQ, Shen Y, Tong WM: Analysis of genetic variants of the poly(ADP-ribose) polymerase-1 gene in breast cancer in French patients. Mutation research 2007, 632(1-2):20-28.View Article  PubMed