| Literature DB >> 25453754 |
Kristen L Karlin1, Gourish Mondal2, Jessica K Hartman3, Siddhartha Tyagi3, Sarah J Kurley3, Chris S Bland3, Tiffany Y T Hsu1, Alexander Renwick4, Justin E Fang5, Ilenia Migliaccio6, Celetta Callaway7, Amritha Nair3, Rocio Dominguez-Vidana1, Don X Nguyen8, C Kent Osborne6, Rachel Schiff6, Li-Yuan Yu-Lee9, Sung Y Jung5, Dean P Edwards7, Susan G Hilsenbeck10, Jeffrey M Rosen9, Xiang H-F Zhang11, Chad A Shaw4, Fergus J Couch2, Thomas F Westbrook12.
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.Entities:
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Year: 2014 PMID： 25453754 PMCID： PMC4427000 DOI： 10.1016/j.celrep.2014.10.011
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423