Abstract 1160: Down-regulation of ATM gene is associated with worse prognosis in sporadic breast carcinomas

Abstract

Abstract Background: Ataxia telangiectasia mutated (ATM) gene encodes a protein associated with DNA damage repair that plays an important role in the maintenance of genome integrity. ATM mutations have been associated with moderate risk of breast cancer (BC), however, this association in sporadic cancers is controversial. Decreased ATM expression in sporadic breast tumors has been reported, but the mechanisms involved in the ATM deregulation are not well established. Recent reports suggests that ATM gene can be regulated by microRNA (miRNA). Aim: The purpose of the present study was to evaluate ATM gene and protein expression in BC samples, correlate the expression levels with its predicted putative miRNA regulators and associate the findings with clinical data. Patients and methods: Fresh ductal invasive BC samples (n=52) and normal breast samples obtained from breast reduction surgery were evaluated for ATM and miR-26a, miR-26b, miR-203, miR-421, miR-664 and miR-576-5p expression by RT-qPCR. ATM protein expression detected by immunohistochemistry was assessed in formalin-fixed, paraffin-embedded (FFPE) ductal invasive BC samples arranged in four tissue microarrays from an independent cohort with long-term follow-up (n=815) and two normal breast samples. Results: Down expression of ATM transcripts was detected in 33% of tumors compared with normal samples (median relative expression=0.63). Additionally, absence of ATM protein expression was detected in 61% (502 out of 820) of tumor tissues. miRNA analysis showed a significant negative correlation between miR-664 with ATM gene expression (P=0.035 and r=−0.293), suggesting that this miRNA might regulate ATM expression. Marginally significant lower ATM mRNA levels were detected in HER2-positive tumors (P=0.048). Moreover, significant decrease of ATM expression was associated with increasing tumor grade, both in transcript and protein levels (P=0.005 and P=0.022, respectively). Absence of ATM protein expression was significantly associated distant metastasis (P<0.001, RR=1.279) and with reduced disease-free survival (DFS, P<0.0001) and cancer-specific survival (CSF, P<0.0001). Further multivariate analysis showed that ATM expression is an independent prognostic factor for DFS and CSF in breast carcinomas (P=0.001, HR=0.567, CI95%=0.410-0.785 and P=0.001, HR=0.567, CI95%=0.404-0.705). Conclusions: Decreased expression of ATM was associated with worse outcome and could be considered a prognostic marker in invasive ductal breast carcinomas. Our data also suggest that ATM aberrant expression can be in part explained by deregulated miRNAs in these tumors, including miR-664, by direct transcripts degradation or translation inhibition. Further functional analyses, including evaluation of other microRNAs, are necessary to confirm these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1160. doi:1538-7445.AM2012-1160