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Sci. Signal., 16 August 2011
Vol. 4, Issue 186, p. pt5
[DOI: 10.1126/scisignal.2002258]

PRESENTATIONS

miR-221/222 Targeting of Trichorhinophalangeal 1 (TRPS1) Promotes 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, USA.
2 Department of Development Oncology Diagnostics, Genentech, Inc., South San Francisco, CA, USA.
3 Center for Bioinformatics and Molecular Biostatistics, University of California San Francisco, San Francisco, CA, USA.
4 Department of Bioinformatics, Genentech, Inc., South San Francisco, CA, USA.
5 Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA.
6 Department of Pathology, Genentech, Inc., South San Francisco, CA, USA.
7 Department of Biostatistics, Genentech, Inc., South San Francisco, CA, USA.

* These authors contributed equally to this work

A presentation from the Keystone Symposium on Epithelial Plasticity and Epithelial to Mesenchymal Transition, Vancouver, Canada, 21 to 26 January 2011. This Presentation also complements the Science Signaling Research Article by Stinson et al. published 14 June 2011.

Abstract: Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expression of epithelial-specific genes and increase expression of mesenchymal-specific genes. In addition, expression of these miRNAs increased cell migration and invasion, which collectively are characteristics of the epithelial-to-mesenchymal transition (EMT). The basal-like transcription factor FOSL1 (also known as Fra-1) directly stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. The miR-221/222–mediated reduction in E-cadherin abundance depended on their targeting of the 3' untranslated region (3'UTR) of TRPS1 (trichorhinophalangeal syndrome type 1), which is a member of the GATA family of transcriptional repressors. TRPS1 inhibited EMT by directly repressing expression of ZEB2 (Zinc finger E-box–binding homeobox 2). Therefore, miR-221/222 may contribute to the aggressive clinical behavior of basal-like breast cancers.

{dagger} Presenter and corresponding author. 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, miR-221/222 Targeting of Trichorhinophalangeal 1 (TRPS1) Promotes Epithelial-to-Mesenchymal Transition in Breast Cancer. Sci. Signal. 4, pt5 (2011).

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