Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer
2014 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 14, 3983-3994 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
American Association for Cancer Research , 2014. Vol. 74, no 14, 3983-3994 p.
IdentifiersURN: urn:nbn:se:liu:diva-109370DOI: 10.1158/0008-5472.CAN-13-3396ISI: 000338875000031PubMedID: 24830720OAI: oai:DiVA.org:liu-109370DiVA: diva2:738064