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Biological and clinical significance of PARP1 protein expression in breast cancer.

Green AR, Caracappa D, Benhasouna AA, Alshareeda A, Nolan CC, Macmillan RD, Madhusudan S, Ellis IO, Rakha EA - Breast Cancer Res. Treat. (2014)

Bottom Line: Negative association was found between PARP1nc and Ki67.PARP1c was associated with ER (p < 0.001).Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, University of Nottingham, Hucknall Road, Nottingham, NG5 1PB, UK, andrew.green@nottingham.ac.uk.

ABSTRACT
Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the treatment of solid tumours including breast cancer (BC). However, the biological and clinical significance of PARP1 expression in BC and its role in DNA-damage response (DDR) remain to be defined. We investigated the expression of PARP1 expression, cleaved (PARP1c) and non-cleaved (PAR1nc) forms, in a large and well-characterised cohort of clinically annotated stage I-III operable BCs (n = 1,269) and 43 BRCA1-mutated BCs using immunohistochemistry. PARP1 expression was correlated to clinicopathological variables, outcome and expression of other key DNA repair proteins (BRCA1, RAD51, Ku70/80, PIASγ and CHK1). Expression of PARP1 was exclusively nuclear. 49 and 85 % of sporadic BC showed expression PARP1nc and PARP1c, respectively. In BRCA1-mutated tumours, PARP1nc/PARP1c was highly expressed (95 and 79 %, respectively). PARP1nc expression was positively associated with premenopausal younger age patients, larger size and higher tumour grade. PARP1 was positively associated with DDR-proteins; RAD51, BRCA1, CHK1 and PIASγ (p < 0.001). Negative association was found between PARP1nc and Ki67. PARP1c was associated with ER (p < 0.001). Different associations between PARP1 and DDR-proteins were observed when stratified based on ER/BRCA1 status. PARP1 was not an independent predictor of outcome in sporadic or BRCA1-mutated BC. Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins. These associations were not restricted to ER-negative or triple-negative subgroup.

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Related in: MedlinePlus

Expression of a PARP1 non-cleaved b PARP1 cleaved protein expression. Normal breast tissue showing weak expression with tumour showing strong expression ×20
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Fig1: Expression of a PARP1 non-cleaved b PARP1 cleaved protein expression. Normal breast tissue showing weak expression with tumour showing strong expression ×20

Mentions: In this study, the expression of PARP1 protein including the non-cleaved/active (PARP1nc) and the cleaved (PARP1c) forms were assessed immunohistochemically and correlated with clinicopathological variables, expression of key biomarkers with relevance to breast cancer, DNA repair markers and patient outcome. Both PARP1 protein forms (PARP1c and PARP1nc) were observed only in the nuclei with no cytoplasmic or membranous expression. Expression of PARP1c and PARP1nc were observed in the normal parenchymal cells of the entrapped normal tissue but their expression was upregulated in malignant cells (Fig. 1). Only nuclear expression in the malignant cells was considered in this study Fig. 2.Fig. 1


Biological and clinical significance of PARP1 protein expression in breast cancer.

Green AR, Caracappa D, Benhasouna AA, Alshareeda A, Nolan CC, Macmillan RD, Madhusudan S, Ellis IO, Rakha EA - Breast Cancer Res. Treat. (2014)

Expression of a PARP1 non-cleaved b PARP1 cleaved protein expression. Normal breast tissue showing weak expression with tumour showing strong expression ×20
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4308637&req=5

Fig1: Expression of a PARP1 non-cleaved b PARP1 cleaved protein expression. Normal breast tissue showing weak expression with tumour showing strong expression ×20
Mentions: In this study, the expression of PARP1 protein including the non-cleaved/active (PARP1nc) and the cleaved (PARP1c) forms were assessed immunohistochemically and correlated with clinicopathological variables, expression of key biomarkers with relevance to breast cancer, DNA repair markers and patient outcome. Both PARP1 protein forms (PARP1c and PARP1nc) were observed only in the nuclei with no cytoplasmic or membranous expression. Expression of PARP1c and PARP1nc were observed in the normal parenchymal cells of the entrapped normal tissue but their expression was upregulated in malignant cells (Fig. 1). Only nuclear expression in the malignant cells was considered in this study Fig. 2.Fig. 1

Bottom Line: Negative association was found between PARP1nc and Ki67.PARP1c was associated with ER (p < 0.001).Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, University of Nottingham, Hucknall Road, Nottingham, NG5 1PB, UK, andrew.green@nottingham.ac.uk.

ABSTRACT
Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the treatment of solid tumours including breast cancer (BC). However, the biological and clinical significance of PARP1 expression in BC and its role in DNA-damage response (DDR) remain to be defined. We investigated the expression of PARP1 expression, cleaved (PARP1c) and non-cleaved (PAR1nc) forms, in a large and well-characterised cohort of clinically annotated stage I-III operable BCs (n = 1,269) and 43 BRCA1-mutated BCs using immunohistochemistry. PARP1 expression was correlated to clinicopathological variables, outcome and expression of other key DNA repair proteins (BRCA1, RAD51, Ku70/80, PIASγ and CHK1). Expression of PARP1 was exclusively nuclear. 49 and 85 % of sporadic BC showed expression PARP1nc and PARP1c, respectively. In BRCA1-mutated tumours, PARP1nc/PARP1c was highly expressed (95 and 79 %, respectively). PARP1nc expression was positively associated with premenopausal younger age patients, larger size and higher tumour grade. PARP1 was positively associated with DDR-proteins; RAD51, BRCA1, CHK1 and PIASγ (p < 0.001). Negative association was found between PARP1nc and Ki67. PARP1c was associated with ER (p < 0.001). Different associations between PARP1 and DDR-proteins were observed when stratified based on ER/BRCA1 status. PARP1 was not an independent predictor of outcome in sporadic or BRCA1-mutated BC. Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins. These associations were not restricted to ER-negative or triple-negative subgroup.

Show MeSH
Related in: MedlinePlus