title: 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.affiliation: Molecular Genetics Laboratory, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: De Summa
authors.affiliation: Molecular Genetics Laboratory, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Pinto
authors.affiliation: Molecular Genetics Laboratory, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Pilato
authors.affiliation: Molecular Genetics Laboratory, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Sambiasi
authors.affiliation: Preclinical and Clinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Porcelli
authors.affiliation: Department of Medical Biochemistry, Medical Biology and Medical Physics, School of Medicine, University of Bari, Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Guida
authors.affiliation: Anatomopathology Unit, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mattioli
authors.affiliation: Experimental Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Paradiso
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo delle Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Merla
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo delle Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Micale
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo delle Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: P
authors.initials: P
authors.lastname: De Nittis
authors.affiliation: Molecular Genetics Laboratory, National Cancer Research Centre, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Tommasi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019295:Computational Biology; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase