Deficiencies in the ATM gene are the underlying cause for
ataxia telangiectasia, a syndrome characterized by neurological, motor and immunological defects, and a predisposition to
cancer.
MicroRNAs (
miRNAs) are useful tools for
cancer profiling and prediction of therapeutic responses to clinical regimens. We investigated the consequences of ATM deficiency on
miRNA expression and associated gene expression in normal human mammary epithelial cells (HME-CCs). We identified 81 significantly differentially expressed
miRNAs in ATM-deficient HME-CCs using small
RNA sequencing. Many of these have been implicated in
tumorigenesis and proliferation and include down-regulated
tumor suppressor
miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as over-expressed pro-oncogenic
miRNAs, such as
hsa-miR-93 and hsa-miR-221.
MicroRNA changes were integrated with genome wide gene expression profiles to investigate possible
miRNA targets. Predicted
mRNA targets of the
miRNAs significantly regulated after ATM depletion included many genes associated with
cancer formation and progression, such as SOCS1 and the proto-oncogene MAF. While a number of
miRNAs have been reported as altered in cancerous cells, there is little understanding as to how these small RNAs might be driving
cancer formation or how they might be used as
biomarkers for
cancer susceptibility. This study provides preliminary data for defining
miRNA profiles that may be used as prognostic or predictive
biomarkers for
breast cancer. Our integrated analysis of
miRNA and
mRNA expression allows us to gain a better understanding of the signaling involved in
breast cancer predisposition and suggests a mechanism for the
breast cancer-prone phenotype seen in ATM-deficient patients.