Abstract
IntroductionMutations 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.MethodsWe 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.ResultsWhile 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).ConclusionsOur 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.
Highlights
Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNAdamaging chemotherapy in breast cancer
While Chk2 activates multiple downstream targets in addition to p53, and the p53 protein may be activated through multiple post-transcriptional events [17], the finding that checkpoint kinase 2 (CHEK2) mutations may substitute for TP53 mutations as a cause of chemo-resistance indicates Chk2 phosphorylation of the p53 protein to play a pivotal role executing cell death in response to anthracycline therapy in breast cancer
Cohort 1 (n = 71) included a selection of 36 out of 91 patients enrolled in a prospective study exploring the mechanisms of resistance to treatment with doxorubicin in locally advanced breast cancer [10] as well as all 35 patients from a similar prospective study evaluating the mechanisms of resistance to 5-fluorouracil and mitomycin (FUMI) [9]
Summary
Mutations affecting p53 or its upstream activator Chk are associated with resistance to DNAdamaging chemotherapy in breast cancer. Excluding potential correlations between genetic and epigenetic alterations affecting cyclin-inhibitors and therapy resistance [8,13,14], subsequently, we detected non-sense mutations in the CHEK2 gene (coding for the Chk protein) in three patients with primary breast cancers revealing anthracycline resistance [8,15]. While Chk activates multiple downstream targets in addition to p53, and the p53 protein may be activated through multiple post-transcriptional events [17], the finding that CHEK2 mutations may substitute for TP53 mutations as a cause of chemo-resistance indicates Chk phosphorylation of the p53 protein to play a pivotal role executing cell death in response to anthracycline therapy in breast cancer
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
