Regulation of Survival by IKKe 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 IkB kinase (IKK) related-kinase IKK drives a specific subset of TNBC and 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-kB and STAT activation and disrupts expression ofthe pro-tumorigenic cytokines CCL5 and IL-6 in these breast cancer cells. When CYT387 is combined with MEK inhibition, mouse models of triple negative breast cancer (TNBC) are effectively treated. As CYT387 and MEK inhibitors are already in advanced human clinical trials, this combination therapy has the potential to make apositive impact on patients suffering from TNBC.

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Document Details

Document Type
Technical Report
Publication Date
Feb 01, 2016
Accession Number
AD1008277

Entities

People

  • Thanh Barbie

Organizations

  • Dana–Farber Cancer Institute

Tags

DTIC Thesaurus Topics

  • Breast Cancer
  • Cell Physiological Processes
  • Cells
  • Chemical Synthesis
  • Chemistry
  • Clinical Trials
  • Combination Therapy
  • Culture Techniques
  • Epithelial Cells
  • Health Services
  • Medical Personnel
  • Molecules
  • Neoplasms
  • Oncology
  • Peptide Growth Factors
  • Proteins
  • Therapy

Fields of Study

  • Medicine

Readers

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