Abstract LB-461: Genome-wide small RNA sequencing and gene expression analysis reveals a microRNA profile reflective of cancer-susceptibility in ATM deficient human mammary epithelial cells

Abstract

Abstract MicroRNAs (miRNAs) are small regulators of post-transcriptional gene expression. miRNAs have recently been shown to be useful in diagnosis, identification of stages, and prediction of response to therapeutics in cancers. In particular, miRNAs have been used to develop signatures for breast cancer profiling. Individuals with deficiencies in ATM have severe ataxia and immunological problems and are predisposed to elevated risks of developing lymphoproliferative and breast cancers. However, deficiencies in the ATM protein generally have not been observed in breast cancer populations. In this study we investigate the effect of the loss of ATM on the miRNA expression in normal, non-cancerous human mammary epithelial cells (HME-CC). Understanding the composition and expression of miRNAs in an ATM-deficient mammary epithelial cell could highlight mechanisms and physiology through which tumor formation proceeds. Using Illumina next-generation sequencing technology, we sequenced small RNAs from wild type and ATM-deficient non-cancerous HME-CCs at the genome-wide level. Additionally, genome-wide messenger RNA (mRNA) gene expression microarray analysis has been performed on these same RNA samples from these cells in order to facilitate the identification of ATM-dependent targets of differentially expressed miRNAs. After processing of the sequencing data, we identified 81 significantly regulated miRNAs in the ATM-deficient HME-CCs. Many of these differential expressed miRNAs have known functions and have been described to be involved in cancer formation and proliferation. These changes include down-regulation of tumor suppressor miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as the over-expression of pro-oncogenic miRNAs hsa-miR-93 and hsa-mir-221. All 81 miRNAs were combined with genome wide gene expression to investigate possible targets of miRNA regulation. Through TargetScan analysis, we identified possible mRNA targets that were also significantly regulated after the loss of ATM. Predicted targets included many genes implicated in cancer formation and progression, including SOCS1 and the proto-oncogene MAF. Identification of these predicted targets with significant gene expression alterations has helped us to build a more complete understanding of the cellular effects on miRNA expression after the loss of ATM. This study highlights miRNA composition and expression changes in ATM-deficient HME-CCs that suggest a mechanism for the breast cancer-prone phenotype seen in ATM deficient cells and patients. Additionally, this study provides preliminary data to suggesting miRNAs may be used as biomarkers to help to determine susceptibility to breast cancer. 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 LB-461. doi:1538-7445.AM2012-LB-461