The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor

Kristen L. Karlin, Gourish Mondal, Jessica K. Hartman, Siddhartha Tyagi, Sarah J. Kurley, Chris S. Bland, Tiffany Y.T. Hsu, Alexander Renwick, Justin E. Fang, Ilenia Migliaccio, Celetta Callaway, Amritha Nair, Rocio Dominguez-Vidana, Don X. Nguyen, C. Kent Osborne, Rachel Schiff, Li Yuan Yu-Lee, Sung Y. Jung, Dean P. Edwards, Susan G. HilsenbeckJeffrey M. Rosen, Xiang H.F. Zhang, Chad A. Shaw, Fergus J. Couch, Thomas F. Westbrook

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase βTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

Original languageEnglish (US)
Pages (from-to)1318-1332
Number of pages15
JournalCell reports
Volume9
Issue number4
DOIs
StatePublished - Nov 20 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Karlin, K. L., Mondal, G., Hartman, J. K., Tyagi, S., Kurley, S. J., Bland, C. S., Hsu, T. Y. T., Renwick, A., Fang, J. E., Migliaccio, I., Callaway, C., Nair, A., Dominguez-Vidana, R., Nguyen, D. X., Osborne, C. K., Schiff, R., Yu-Lee, L. Y., Jung, S. Y., Edwards, D. P., ... Westbrook, T. F. (2014). The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor. Cell reports, 9(4), 1318-1332. https://doi.org/10.1016/j.celrep.2014.10.011