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Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.

Authors
  • Zhao, Chunyan
  • Qiao, Yichun
  • Jonsson, Philip
  • Wang, Jian
  • Xu, Li
  • Rouhi, Pegah
  • Sinha, Indranil
  • Cao, Yihai
  • Williams, Cecilia
  • Dahlman-Wright, Karin
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jul 15, 2014
Volume
74
Issue
14
Pages
3983–3994
Identifiers
DOI: 10.1158/0008-5472.CAN-13-3396
PMID: 24830720
Source
Medline
License
Unknown

Abstract

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.

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