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. 2011 Jun 14;4(177):ra41.
doi: 10.1126/scisignal.2001538.

TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer

Susanna Stinson  1 , Mark R Lackner, Alex T Adai, Nancy Yu, Hyo-Jin Kim, Carol O'Brien, Jill Spoerke, Suchit Jhunjhunwala, Zachary Boyd, Thomas Januario, Robert J Newman, Peng Yue, Richard Bourgon, Zora Modrusan, Howard M Stern, Søren Warming, Frederic J de Sauvage, Lukas Amler, Ru-Fang Yeh, David Dornan
Affiliations

TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer

Susanna Stinson et al. Sci Signal. .

Abstract

The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to-mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra-1), which is found in basal-like breast cancers but not in the luminal subtype, stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. Furthermore, miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting the 3' untranslated region of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1), which inhibited EMT by decreasing ZEB2 (zinc finger E-box-binding homeobox2) expression. We conclude that by promoting EMT, miR-221/222 may contribute to the more aggressive clinical behavior of basal-like breast cancers.

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