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Sci. Signal., 14 June 2011
Vol. 4, Issue 177, p. ra41
[DOI: 10.1126/scisignal.2001538]

RESEARCH ARTICLES

TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer

Susanna Stinson1*, Mark R. Lackner2*, Alex T. Adai3*, Nancy Yu1, Hyo-Jin Kim1, Carol O’Brien2, Jill Spoerke2, Suchit Jhunjhunwala4, Zachary Boyd2, Thomas Januario1, Robert J. Newman5, Peng Yue4, Richard Bourgon4, Zora Modrusan5, Howard M. Stern6, Søren Warming5, Frederic J. de Sauvage5, Lukas Amler2, Ru-Fang Yeh7, and David Dornan1{dagger}

1 Department of Molecular Diagnostics and Cancer Cell Biology, Genentech Inc., South San Francisco, CA 94080, USA.
2 Department of Development Oncology Diagnostics, Genentech Inc., South San Francisco, CA 94080, USA.
3 Center for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, CA 94143, USA.
4 Department of Bioinformatics, Genentech Inc., South San Francisco, CA 94080, USA.
5 Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
6 Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
7 Department of Biostatistics, Genentech Inc., South San Francisco, CA 94080, USA.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: dornan.david{at}gene.com

Citation: S. Stinson, M. R. Lackner, A. T. Adai, N. Yu, H.-J. Kim, C. O’Brien, J. Spoerke, S. Jhunjhunwala, Z. Boyd, T. Januario, R. J. Newman, P. Yue, R. Bourgon, Z. Modrusan, H. M. Stern, S. Warming, F. J. de Sauvage, L. Amler, R.-F. Yeh, D. Dornan, TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer. Sci. Signal. 4, ra41 (2011).

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