MiRNAs that Define Breast Cancer Phenotypes.

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Abstract
To identify miRNAs associated with estrogen receptor alpha (ER) status in breast cancer, we performed miRNA profiling of ER+ luminal A (MCF7 and T47D) versus ER-triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and BT549). Members of the miR-200 family show the highest fold difference, with miR-200c being 53 fold more abundant in Luminal A type cells. MiR-200c has been shown to be critical to the epithelial phenotype and is always associated with ER positivity. We find that miR-200c represses a program of mesenchymal and neuronal genes which are not normally expressed in epithelial cells, but are aberrantly expressed in carcinoma cells that have undergone epithelial to mesenchymal transition. These include fibronectin, moesin, NTRK2 and class III beta-tubulin, which are involved in migration, invasion, resistance to anoikis, and taxane resistance respectively. Additional miRNAs more abundant in luminal A cells control key genes involved in metabolism. Aggressive breast tumors overexpress the glucose transporter GLUT1, resulting in increased glucose uptake. They also rely on de novo fatty acid synthesis and often overexpress fatty acid synthase (FASN). We demonstrate that miR-193b, miR-15b and miR-103/107 directly target FASN and miR-301 and miR-148a directly target GLUT1. Restoration of these miRNAs to TNBC cells dramatically reduces FASN and GLUT1 protein levels and reduction in FASN leads to apoptosis. Although the majority of differentially expressed miRNAs are higher in luminal A cells, some are higher in TNBC. For instance, miR-222/221 levels are over 90 fold higher in TNBC cell lines and are only expressed in ER negative clinical specimens. Interestingly miR-222/221 and miR-29 (the top miRNAs more abundant in TNBC cells) directly target Dicer itself. Using mimics and inhibitors of these miRNAs we can modulate Dicer protein levels. Lower Dicer levels could explain why most miRNAs are less abundant in TNBC. We also identify miRNAs regulated by estradiol and progesterone. MiR-7 is upregulated by E2 and higher in ER+ cells, and when we increase its levels in TNBC cells, it represses EGFR, IGF1Rbeta and IRS2. Collectively, our data indicate that specific miRNAs control distinguishing characteristics of luminal A versus TNBC and may influence their aggressive clinical behavior. Manipulation of these miRNAs may have potential as a treatment for TNBC, for which there are currently no optimal therapeutics. Nothing to Disclose: DRC, ENH, ELM, BMJ, SMA, JRR

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