Journal
NUCLEIC ACIDS RESEARCH
Volume 46, Issue 3, Pages 1180-1195Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx1190
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Funding
- Swedish Cancer Foundation [09 0773, 10 0452, 2016/445]
- Swedish Research Council [2015-02757]
- Kanae Foundation for Research Abroad
- ITO Genboku and SAGARA Chian Memorial Scholarship
- Japan Society for the Promotion of Science (JSPS)
- KAKENHI [15H05774]
- Swedish Research Council [2015-02757] Funding Source: Swedish Research Council
- Grants-in-Aid for Scientific Research [15H05774] Funding Source: KAKEN
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It is well established that transforming growth factor-beta (TGF beta) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD and other transcription factors define pro-oncogenic events. Here, we have performed chromatin immunoprecipitation (ChIP)-sequencing analyses which indicate that the genome-wide landscape of SMAD2/3 binding is altered after prolonged TGF beta stimulation. De novo motif analyses of the SMAD2/3 binding regions predict enrichment of binding motifs for activator protein (AP) 1 in addition to SMAD motifs. TGF beta-induced expression of the AP1 component JUNB was required for expression of many late invasion-mediating genes, creating a feed-forward regulatory network. Moreover, we found that several components in the WNT pathway were enriched among the late TGF beta-target genes, including the invasion-inducing WNT7 proteins. Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGF beta-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process. Our study thereby helps to explain how accumulation of pro-oncogenic stimuli switches and stabilizes TGF beta-induced cellular phenotypes of epithelial cells.
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