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

J. B. Patel, H. N. Appaiah, R. M. Burnett, P. Bhat-Nakshatri, G. Wang, R. Mehta, S. Badve, M. J. Thomson, S. Hammond, P. Steeg, Y. Liu, H. Nakshatri

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1290-1301
Number of pages12
JournalOncogene
Volume30
Issue number11
DOIs
StatePublished - Mar 17 2011

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Keywords

  • breast cancer
  • let-7
  • metastasis
  • microRNA
  • miR-22

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

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. (2011). Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22. Oncogene, 30(11), 1290-1301. https://doi.org/10.1038/onc.2010.510