Regulation of Survival by IKK(epsilon) in Inflammatory Breast Cancer Involves EpCAM

Abstract

Although triple negative breast cancers (TNBC) consistently lack hormone receptor expression and ERBB2 amplification, several lines of evidence suggest that these cancers are heterogeneous. Here we find that aberrant expression of the I B kinase (IKK) related-kinase IKK drives a specific subset of TNBC that are maintained by an autocrine cytokine circuit involving JAK/STAT pathway activation. We identify CYT387 as a novel potent inhibitor of IKK and JAK signaling that disrupts this circuit and preferentially impairs the proliferation of IKK -driven breast cancer cells in vitro. CYT387 treatment inhibits both NF- B and STAT activation and disrupts expression of the pro-tumorigenic cytokines CCL5 and IL-6 in these breast cancer cells. Interruption of cytokine signaling by CYT387 in vivo impairs the growth of an IKK -driven TNBC cell line and patient-derived xenografts. These findings elucidate a specific immune-driven subtype of TNBC that is sensitive to combined IKK and JAK inhibition.

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Document Details

Document Type
Technical Report
Publication Date
Dec 01, 2013
Accession Number
ADA612868

Entities

People

  • Thanh Barbie

Organizations

  • Washington University in St. Louis

Tags

DTIC Thesaurus Topics

  • Biomedical Research
  • Breast Cancer
  • Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Cytokines
  • Department Of Defense
  • Diseases And Disorders
  • Gene Expression
  • Inhibition
  • Inhibitors
  • Molecules
  • Neoplasms
  • Small Molecules
  • Survival
  • Xenografts

Fields of Study

  • Medicine

Readers

  • Breast cancer cell signaling and growth regulation.
  • Oncology (Cancer Research).