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Is there a role for base excision repair in estrogen/estrogen receptor-driven breast cancers?

Abdel-Fatah, Tarek M.A.; Perry, Christina; Arora, Arvind; Thompson, Nicola; Doherty, Rachel; Moseley, Paul M.; Green, Andrew R.; Chan, Stephen Y.T.; Ellis, Ian O.; Madhusudan, Srinivasan

Is there a role for base excision repair in estrogen/estrogen receptor-driven breast cancers? Thumbnail


Authors

Tarek M.A. Abdel-Fatah

Christina Perry

Arvind Arora

Nicola Thompson

Rachel Doherty

Paul M. Moseley

Stephen Y.T. Chan



Abstract

Estrogen and estrogen metabolite-induced reactive oxygen species generation can promote oxidative DNA base damage. If unrepaired, base damaging lesions could accelerate mutagenesis, leading to a “mutator phenotype” characterized by aggressive behavior in estrogen-estrogen receptor (ER)-driven breast cancer. To test this hypothesis, we investigated 1406 ER+ early-stage breast cancers with 20 years' long-term clinical follow-up data for DNA polymerase β (pol β), flap endonuclease 1 (FEN1), AP endonuclease 1 (APE1), X-ray cross-complementation group 1 protein (XRCC1), single-strand monofunctional uracil glycosylase-1 (SMUG1), poly (ADP-ribose) polymerase 1 (PARP1), ataxia telangiectasia mutated and Rad3 related (ATR), ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Chk1, Chk2, p53, breast cancer susceptibility gene 1 (BRCA1), and topoisomerase 2 (TOPO2) expression. Multivariate Cox proportional hazards model was used to calculate a DNA repair prognostic index and correlated to clinicopathological variables and survival outcomes. Key base excision repair (BER) proteins, including XRCC1, APE1, SMUG1, and FEN1, were independently associated with poor breast cancer-specific survival (BCSS) (ps≤0.01). Multivariate Cox model stratified patients into four distinct prognostic sub-groups with worsening BCSS (ps≤0.01) ). Multivariate Cox model stratified patients into four distinct prognostic sub-groups with worsening BCSS (ps≤0.01) In addition, compared with prognostic sub-group 1, sub-groups 2, 3, and 4 manifest increasing tumor size, grade, mitosis, pleomorphism, differentiation, lymphovascular invasion, high Ki67, loss of Bcl-2, luminal B phenotype (ps≤0.01) , and poor survival, including in patients who received tamoxifen adjuvant therapy (p≤0.00001). Our observation supports the hypothesis that BER-directed stratification could inform appropriate therapies in estrogen-ER-driven breast cancers.

Citation

Abdel-Fatah, T. M., Perry, C., Arora, A., Thompson, N., Doherty, R., Moseley, P. M., …Madhusudan, S. (2014). Is there a role for base excision repair in estrogen/estrogen receptor-driven breast cancers?. Antioxidants and Redox Signaling, 21(16), 2262-2268. https://doi.org/10.1089/ars.2014.6077

Journal Article Type Article
Acceptance Date Aug 10, 2014
Online Publication Date Sep 22, 2014
Publication Date Nov 7, 2014
Deposit Date Oct 17, 2018
Publicly Available Date Oct 17, 2018
Journal Antioxidants & Redox Signaling
Print ISSN 1523-0864
Electronic ISSN 1557-7716
Publisher Mary Ann Liebert
Peer Reviewed Peer Reviewed
Volume 21
Issue 16
Pages 2262-2268
DOI https://doi.org/10.1089/ars.2014.6077
Keywords Clinical biochemistry; Cell biology; Biochemistry; Physiology; Molecular biology
Public URL https://nottingham-repository.worktribe.com/output/1172138
Publisher URL https://www.liebertpub.com/doi/10.1089/ars.2014.6077