Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22

Metastasis in breast cancer carries a disproportionately worse prognosis than localized primary disease. To identify microRNAs (miRNA) involved in metastasis, the expression of 254 miRNAs

was measured across the following cell lines using microarray analysis: MDA-MB-231 breast cancer cells, cells that grew as a tumor in the mammary fat pad of nude mice (TMD-231), metastatic

disease to the lungs (LMD-231), bone (BMD-231) and adrenal gland (ADMD-231). A brain-seeking variant of this cell line (231-BR) was used additionally in validation studies. Twenty miRNAs

were upregulated and seven were downregulated in metastatic cancer cells compared with TMD-231 cells. The expression of the tumor suppressor miRNAs let-7 and miR-22 was consistently

downregulated in metastatic cancer cells. These metastatic cells expressed higher levels of putative/proven miR-22 target oncogenes ERBB3, CDC25C and EVI-1. Introduction of miR-22 into

cancer cells reduced the levels of ERBB3 and EVI-1 as well as phospho-AKT, an EVI-1 downstream target. The miR-22 primary transcript is located in the 5′-untranslated region of an open

reading frame C17orf91, and the promoter/enhancer of C17orf91 drives miR-22 expression. We observed elevated C17orf91 expression in non-basal subtype compared with basal subtype breast

cancers. In contrast, elevated expression of EVI-1 was observed in basal subtype and was associated with poor outcome in estrogen receptor-negative breast cancer patients. These results

suggest that metastatic cancer cells increase specific oncogenic signaling proteins through downregulation of miRNAs. Identifying such metastasis-specific oncogenic pathways may help to

manipulate tumor behavior and aid in the design of more effective targeted therapies.

This work is supported by Indiana University Simon Cancer Center Pilot grant and by Komen for Cure grant BCTR0601111 to HN. JBP and RMB are supported by National Institutes of Health

Training Grants T32 DK07519 and T32 CA111198, respectively. HN is Marian J Morrison Professor of Breast Cancer Research.

J B Patel and H N Appaiah: These authors contributed equally to this work.

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

J B Patel, H N Appaiah, R M Burnett, P Bhat-Nakshatri & H Nakshatri

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA

Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical School, Nashville, TN, USA

Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

Laboratory of Molecular Pharmacology, Center for Cancer Research National Cancer Institute, Bethesda, MD, USA

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

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