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

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.

Figure 1

(A) Western blot of ATM expression in breast cancer cell lines. (B) Western blot of Chk2 expression in breast cancer cell lines. (C) Microphotograph of ATM and Chk2 negative and positive breast cancer tissue. (D) Kaplan-Meier curves showing BCSS and ATM level. (E) Kaplan-Meier curves showing BCSS and Chk2 level.

Figure 2

(A) Kaplan-Meier curves showing BCSS stratified based on p53 mutation status and ATM level. (B) Kaplan-Meier curves showing BCSS stratified based on p53 mutation status and Chk2 level. (C) Kaplan-Meier curves showing BCSS stratified based on ATM and Chk2 coexpression.

Figure 3

(A) Kaplan-Meier curves showing BCSS based on ATM levels in ER − patients who received anthracycline chemotherapy. (B) Kaplan-Meier curves showing BCSS based on ATM levels in ER − patients who received CMF chemotherapy. (C) Kaplan-Meier curves showing BCSS based on ATM levels in ER + patients who received endocrine therapy. (D) Kaplan-Meier curves showing BCSS based on ATM mRNA expression in the whole cohort. (E) Kaplan-Meier curves showing BCSS based on ATM mRNA expression in ER − patients who received chemotherapy. (F) Kaplan-Meier curves showing BCSS based on ATM mRNA expression in ER + patients who received endocrine therapy.

Figure 4

(A) Kaplan-Meier curves showing BCSS based on Chk2 levels in ER − patients who received anthracycline chemotherapy. (B) Kaplan-Meier curves showing BCSS based on Chk2levels in ER − patients who received CMF chemotherapy. (C) Kaplan-Meier curves showing BCSS based on Chk2 levels in ER + patients who received endocrine therapy. (D) Kaplan-Meier curves showing BCSS based on Chk2 mRNA expression in the whole cohort. (E) Kaplan-Meier curves showing BCSS based on Chk2 mRNA expression in ER − patients who received chemotherapy. (F) Kaplan-Meier curves showing BCSS based on Chk2 mRNA expression in ER + patients who received endocrine therapy.