The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor

Cell Rep. 2014 Nov 20;9(4):1318-32. doi: 10.1016/j.celrep.2014.10.011. Epub 2014 Nov 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis / pathology
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / pathology
  • Female
  • Gene Amplification
  • Humans
  • Mice
  • Neoplasm Metastasis
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins / metabolism
  • Repressor Proteins / metabolism*
  • Signal Transduction*
  • Transcription, Genetic
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology*

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1