Accession Number:

ADA621084

Title:

Regulation of Survival by IKKE in Inflammatory Breast Cancer Involves EpCAM

Descriptive Note:

Annual rept. 1 Dec 2013-30 Jun 2014

Corporate Author:

WASHINGTON UNIV ST LOUIS MO

Personal Author(s):

Report Date:

2014-07-01

Pagination or Media Count:

12.0

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 kappa B kinase IKK related-kinase IKK epsilon drives a specific subset of TNBC that are maintained by an autocrine cytokine circuit involving JAKSTAT pathway activation. We identify CYT387 as a novel potent inhibitor of IKK epsilon and JAK signaling that disrupts this circuit and preferentially impairs the proliferation of IKK epsilon-driven breast cancer cells in vitro. CYT387 treatment inhibits both NF-kappa 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 epsilon-driven TNBC cell line and patient-derived xenografts. These findings elucidate a specific immune-driven subtype of TNBC that is sensitive to combined IKK epsilon and JAK inhibition.

Subject Categories:

  • Biochemistry
  • Biology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE