Research ArticleCancer

EGF induces microRNAs that target suppressors of cell migration: miR-15b targets MTSS1 in breast cancer

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Sci. Signal.  17 Mar 2015:
Vol. 8, Issue 368, pp. ra29
DOI: 10.1126/scisignal.2005866

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Micromanaging growth factor–induced metastasis

Epidermal growth factor (EGF) stimulates cell proliferation and tumor growth in part by triggering kinase-dependent changes in gene expression. Noncoding RNAs, such as microRNAs (miRNAs), reduce gene expression by binding to protein-encoding transcripts. Kedmi et al. found that EGF stimulated migration in mammary epithelial cells and also increased the abundance of a set of miRNAs. Of these, miR-15b promoted EGF-induced migration and reduced the abundance of metastasis suppressor protein 1 (MTSS1). The expression of miR-15b was higher in aggressive tumors than in adjacent normal tissue and inversely correlated with that of MTSS1. Knockdown of MTSS1 promoted the migratory behavior and the formation of migration-associated structures in cultured cells. Low abundance of MTSS1 correlated with shorter survival in patients, and low expression of MTSS1 correlated with high expression of miR-15b in aggressive basal breast cancer tissue, suggesting that this pathway is important in breast cancer and could be targeted to reduce metastatic disease in patients.


Growth factors promote tumor growth and metastasis. We found that epidermal growth factor (EGF) induced a set of 22 microRNAs (miRNAs) before promoting the migration of mammary cells. These miRNAs were more abundant in human breast tumors relative to the surrounding tissue, and their abundance varied among breast cancer subtypes. One of these miRNAs, miR-15b, targeted the 3′ untranslated region of MTSS1 (metastasis suppressor protein 1). Although xenografts in which MTSS1 was knocked down grew more slowly in mice initially, longer-term growth was unaffected. Knocking down MTSS1 increased migration and Matrigel invasion of nontransformed mammary epithelial cells. Overexpressing MTSS1 in an invasive cell line decreased cell migration and invasiveness, decreased the formation of invadopodia and actin stress fibers, and increased the formation of cellular junctions. In tissues from breast cancer patients with the aggressive basal subtype, an inverse correlation occurred with the high expression of miRNA-15b and the low expression of MTSS1. Furthermore, low abundance of MTSS1 correlated with poor patient prognosis. Thus, growth factor–inducible miRNAs mediate mechanisms underlying the progression of cancer.

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