Expression of base excision repair key factors and miR17 in familial and sporadic breast cancer.

Abstract	Understanding of BRCA1/2 interaction with the base excision repair (BER) pathway could improve therapy based on 'synthetic lethality', whose effectiveness is based on homologous recombination deficiency in cells lacking functional BRCA genes. However, poly (ADP-ribose) polymerase (PARP) inhibitors failed in some patients and for this reason we explored BER key enzyme expression. In this study, the expression of BER enzymes (redox factor 1/apurinic-apyrimidinic endonuclease 1 (REF1/APEX1), NTH endonuclease III-like 1 (NTHL1), 8-oxoguanine DNA glycosylase (OGG1), PARP1) and of the scaffold protein XRCC1 (X-ray repair complementing defective repair in Chinese hamster cells 1) were investigated in familial (BRCA-related and not) and sporadic breast cancer cases. Furthermore, miR17 expression was measured because of its role in the epigenetic regulation of BRCA1. Gene expression was evaluated in BRCA1-mutated cell lines, SUM149PT and SUM1315MO2, and in a BRCA1-proficient triple-negative MDA-MB-231 cell line. A cohort of 27 familial and 16 sporadic breast cancer patients was then examined to confirm results obtained from the cell line model. APEX1/REF1 was found to be upregulated in familial BRCA-wild-type and sporadic cases, indicating this enzyme as a potential therapeutic target. Furthermore, XRCC1 was overexpressed in BRCAX patients; consequently, we suggest to test the effectiveness of inhibitors targeting two different BER components in preclinical studies. XRCC1, which is also involved in the non-homologous end-joining pathway, was found to be downregulated in BRCA2-related patients concurrently with no change in PARP1 expression. Interestingly, no difference in PARP1 and miR17 expression was found in BRCA-related and sporadic breast cancer cases. PARP1 and miR17 could therefore be further investigated as molecular biomarkers of 'BRCAness' phenotype, indicating patients which could really benefit from PARP inhibitor therapies.
Authors	S De Summa, R Pinto, B Pilato, D Sambiasi, L Porcelli, G Guida, E Mattioli, A Paradiso, G Merla, L Micale, P De Nittis, S Tommasi
Journal	Cell death & disease (Cell Death Dis) Vol. 5 Pg. e1076 (Feb 20 2014) ISSN: 2041-4889 [Electronic] England
PMID	24556691 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	BRCA1 Protein BRCA1 protein, human BRCA2 Protein BRCA2 protein, human Biomarkers, Tumor DNA-Binding Proteins MIRN17 microRNA, human MicroRNAs X-ray Repair Cross Complementing Protein 1 XRCC1 protein, human Xrcc1 protein, mouse PARP1 protein, human Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases Deoxyribonuclease (Pyrimidine Dimer) NTHL1 protein, human DNA Glycosylases oxoguanine glycosylase 1, human APEX1 protein, human DNA-(Apurinic or Apyrimidinic Site) Lyase
Topics	Adult Aged Animals BRCA1 Protein (genetics) BRCA2 Protein (genetics) Biomarkers, Tumor (genetics, metabolism) Cell Line, Tumor Computational Biology DNA Glycosylases (genetics, metabolism) DNA Repair (genetics) DNA-(Apurinic or Apyrimidinic Site) Lyase (genetics, metabolism) DNA-Binding Proteins (genetics, metabolism) Databases, Genetic Deoxyribonuclease (Pyrimidine Dimer) (genetics, metabolism) Female Genetic Predisposition to Disease HEK293 Cells Humans Mice MicroRNAs (metabolism) Middle Aged Mutation Phenotype Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases (genetics, metabolism) Transfection Triple Negative Breast Neoplasms (genetics, metabolism, pathology) X-ray Repair Cross Complementing Protein 1

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