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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere1076
JournalCell Death and Disease
Volume5
Issue number2
DOIs
Publication statusPublished - Feb 2014

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DNA Repair
Breast Neoplasms
Cell Line
Enzymes
DNA-(Apurinic or Apyrimidinic Site) Lyase
DNA Glycosylases
Endonucleases
Homologous Recombination
Cricetulus
Epigenomics
Oxidation-Reduction
Therapeutics
Down-Regulation
Biomarkers
X-Rays
Familial Breast Cancer
Phenotype
Gene Expression
Genes
Poly(ADP-ribose) Polymerase Inhibitors

Keywords

  • APEX1/REF1
  • base excision repair
  • familial breast cancer
  • miR17
  • PARP1
  • XRCC1

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Expression of base excision repair key factors and miR17 in familial and sporadic breast cancer. / De Summa, S.; Pinto, R.; Pilato, B.; Sambiasi, D.; Porcelli, L.; Guida, G.; Mattioli, E.; Paradiso, A.; Merla, G.; Micale, L.; De Nittis, P.; Tommasi, S.

In: Cell Death and Disease, Vol. 5, No. 2, e1076, 02.2014.

Research output: Contribution to journalArticle

De Summa, S. ; Pinto, R. ; Pilato, B. ; Sambiasi, D. ; Porcelli, L. ; Guida, G. ; Mattioli, E. ; Paradiso, A. ; Merla, G. ; Micale, L. ; De Nittis, P. ; Tommasi, S. / Expression of base excision repair key factors and miR17 in familial and sporadic breast cancer. In: Cell Death and Disease. 2014 ; Vol. 5, No. 2.
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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.",
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AU - Guida, G.

AU - Mattioli, E.

AU - Paradiso, A.

AU - Merla, G.

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AU - De Nittis, P.

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