Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer.
Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer.
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DOI：
10.1186/bcr3147
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发表时间：
2012-03-15
期刊：
影响因子：
--
通讯作者：
Lønning PE
中科院分区：
文献类型：
--
作者：
Knappskog S;Chrisanthar R;Løkkevik E;Anker G;Østenstad B;Lundgren S;Risberg T;Mjaaland I;Leirvaag B;Miletic H;Lønning PE
影响p53或其上游激活剂Chk 2的突变与乳腺癌对DNA损伤化疗的耐药性相关。ATM（Ataxia Telangiectasia Mutated protein）是p53和Chk 2在遗传毒性应激反应中的关键激活因子。在这里，我们试图评估ATM在化疗耐药性中的潜在作用。我们对71例局部晚期乳腺癌进行了ATM测序，并评估了其治疗前活检组织的基因表达水平，这些乳腺癌在新辅助治疗环境中接受了多柔比星单药治疗或丝裂霉素联合5-氟尿嘧啶治疗。结果在接受表阿霉素单药治疗的单独患者队列中得到证实。先前分析了每个肿瘤的CHEK 2和TP 53突变状态。虽然ATM突变与化疗耐药性无关，但低ATM表达水平预测了TP 53和CHEK 2野生型肿瘤患者的化疗耐药性（P = 0.028）。分析ATM-chk 2-p53级联、低ATM水平（定义为较低的5至50%的阈值）或使TP 53或CHEK 2失活的突变稳健地预测蒽环类抗生素抗性（P值在0.001和0.027之间变化，取决于用于定义“低”ATM水平的百分位数）。这些结果在接受表阿霉素单药治疗的109例患者的独立队列中得到证实。相反，ATM-水平在具有TP 53或CHEK 2突变的耐药肿瘤中未被抑制（P > 0.5）。我们的数据表明，ATM-Chk 2-p53级联功能的丧失与乳腺癌对含蒽环类/丝裂霉素化疗的耐药性密切相关。
Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy. We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status. While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5). Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.
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