ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels

Abstract

Background:Ataxia telangiectasia mutated (ATM) is a kinase that has a central role in the maintenance of genomic integrity by activating cell cycle checkpoints and promoting repair of DNA double-strand breaks (DSB). In breast cancer, a low level of ATM was correlated with poor outcome; however, the molecular mechanism of this downregulation is still unclear.Methods:We used qRT–PCR assay to quantify mRNA levels of ATM gene in 454 breast tumours from patients with known clinical/pathological status and outcome; reverse phase protein arrays (RPPA) were used to assess the levels of ATM and 14 proteins in 233 breast tumours.Results:ATM mRNA was associated with poor metastasis-free survival (MFS) (P=0.00012) on univariate analysis. ATM mRNA and protein levels were positively correlated (P=0.00040). A low level of ATM protein was correlated with poorer MFS (P=0.000025). ATM expression at mRNA or protein levels are independent prognostic factors on multivariate analysis (P=0.00046 and P=0.00037, respectively). The ATM protein level was positively correlated with the levels of six proteins of the DSB repair pathway: H2AX (P<0.0000001), XRCC5 (P<0.0000001), NBN (P<0.0000001), Mre11 (P=0.0000029), Rad50 (P=0.0064), and TP53BP1 (P=0.026), but not with proteins involved in other pathways that are altered in cancer. Low expression of ATM protein was significantly associated with high miR-203 expression (P=0.011).Conclusion:We confirmed that ATM expression is an independent prognostic marker at both RNA and protein levels. We showed that alteration of ATM is involved in dysregulation of the DSB repair pathway. Finally, miR-203 may be responsible for downregulation of ATM in breast cancers.

Noncoding RNAs in breast cancer

“…The protein ataxia telangiectasia mutated (ATM), targeted by miR-18 a, is a kinase that plays a pivotal role in the maintenance of genomic integrity through the activation of cell cycle checkpoints, enhancing repair of DNA doublestrand breaks [56]. A low level of ATM in breast cancer has been shown to correlate with poor outcome [125]. In addition to ATM, BRCA1, targeted by miR-182, is another critical factor involved in maintaining genomic stability through DNA double-stranded break repair [69].…”

Effect of ATM–111 (G>A) Polymorphism on Cancer Risk: A Meta-Analysis

“…It is followed by the activation of cell cycle checkpoints, DNA repair, and apoptosis (Shiloh, 2003;Chaudhary and Al-Baradie, 2014). In fact, ATM is commonly believed to be a tumor-suppressor gene (Rondeau et al, 2015). The downregulation of ATM expression has been correlated with carcinogenesis in a variety of cancers, including prostate cancer (Fan et al, 2006), renal cell carcinoma (Selvarajah et al, 2013), endometrial carcinoma, and more (Shan et al, 2015).…”

miR-30a radiosensitizes non-small cell lung cancer by targeting ATF1 that is involved in the phosphorylation of ATM

“…The main target of IR is cellular DNA, ATM has a key role in the study of IR caused DNA damage (28). In response to DNA damage, by phosphorylation of ATM S1981, a series of downstream molecules can be actived to mediate cell cycle arrest, apoptosis (29) and initiate DNA repair (26).…”