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

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
• Contract Date: Oct 17, 2018