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

• Published in: Oncogene Vol. 30; no. 11; pp. 1290 - 1301
• Main Authors: Patel, J B, Appaiah, H N, Burnett, R M, Bhat-Nakshatri, P, Wang, G, Mehta, R, Badve, S, Thomson, M J, Hammond, S, Steeg, P, Liu, Y, Nakshatri, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-03-2011; Nature Publishing Group
• Subjects: 5' Untranslated Regions; 631/208/200; 631/337/384/331; 692/699/67/1347; 692/699/67/322; Adrenal glands; AKT protein; Animals; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Development and progression; DNA microarrays; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; ErbB-3 protein; Estrogen receptors; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Internal Medicine; Lung diseases; Mammary gland diseases; MDS1 and EVI1 Complex Locus Protein; Medical sciences; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Nude; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; miRNA; Molecular and cellular biology; Neoplasm Metastasis; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Oncogenes; Oncology; original-article; Proteins; Proto-Oncogenes - genetics; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Ribonucleic acid; RNA; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor suppressor genes; Tumors; United States; breast cancer; microRNA; miR-22; let-7; metastasis; Breast disease; RNA interference; Micro RNA; Breast cancer; Malignant tumor; Metastasis; Carcinogenesis; Mammary gland diseases; Gene silencing; Regulation(control); Onc gene; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.510

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.