Clinicopathological significance of ATM-Chk2 expression in sporadic breast cancers: a comprehensive analysis in large cohorts

Abdel-Fatah, Tarek M.A.; Arora, Arvind; Alsubhi, Nouf; Agarwal, Devika; Moseley, Paul M.; Perry, Christina; Doherty, Rachel; Chan, Stephen Y.T.; Green, Andrew R.; Rakha, Emad; Ball, Graham; Ellis, Ian O.; Madhusudan, Srinivasan

Abstract

ATM-Chk2 network is critical for genomic stability, and its deregulation may influence breast cancer pathogenesis. We investigated ATM and Chk2 protein levels in two cohorts [cohort 1 (n = 1650) and cohort 2 (n = 252)]. ATM and Chk2 mRNA expression was evaluated in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1950). Low nuclear ATM protein level was significantly associated with aggressive breast cancer including larger tumors, higher tumor grade, higher mitotic index, pleomorphism, tumor type, lymphovascular invasion, estrogen receptor (ER)−, PR −, AR −, triple-negative, and basal-like phenotypes (Ps < .05). Breast cancer 1, early onset negative, low XRCC1, low SMUG1, high FEN1, high MIB1, p53 mutants, low MDM2, low Bcl-2, low p21, low Bax, high CDK1, and low Chk2 were also more frequent in tumors with low nuclear ATM level (Ps < .05). Low ATM protein level was significantly associated with poor survival including in patients with ER-negative tumors who received adjuvant anthracycline or cyclophosphamide, methotrexate, and 5-fluorouracil–based adjuvant chemotherapy (Ps < .05). Low nuclear Chk2 protein was likely in ER −/PR −/AR −; HER-2 positive; breast cancer 1, early onset negative; low XRCC1; low SMUG1; low APE1; low polβ; low DNA-PKcs; low ATM; low Bcl-2; and low TOPO2A tumors (P < .05). In patients with ER + tumors who received endocrine therapy or ER-negative tumors who received chemotherapy, nuclear Chk2 levels did not significantly influence survival. In p53 mutant tumors, low ATM (P < .000001) or high Chk2 (P < .01) was associated with poor survival. When investigated together, low-ATM/high-Chk2 tumors have the worst survival (P = .0033). Our data suggest that ATM-Chk2 levels in sporadic breast cancer may have prognostic and predictive significance.

Citation

Abdel-Fatah, T. M., Arora, A., Alsubhi, N., Agarwal, D., Moseley, P. M., Perry, C., …Madhusudan, S. (2014). Clinicopathological significance of ATM-Chk2 expression in sporadic breast cancers: a comprehensive analysis in large cohorts. Neoplasia, 16(11), 982-991. https://doi.org/10.1016/j.neo.2014.09.009

• Journal Article Type: Article
• Acceptance Date: Sep 22, 2014
• Online Publication Date: Nov 20, 2014
• Publication Date: 2014-11
• Deposit Date: Oct 17, 2018
• Publicly Available Date: Oct 17, 2018
• Journal: Neoplasia
• Print ISSN: 1522-8002
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 11
• Pages: 982-991
• DOI: https://doi.org/10.1016/j.neo.2014.09.009
• Keywords: Cancer Research
• Public URL: https://nottingham-repository.worktribe.com/output/1172881
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1476558614001444