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JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan..
Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, POB 9600, NL-2300 RC Leiden, Netherlands..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 3, p. 1180-1195Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS , 2018. Vol. 46, no 3, p. 1180-1195
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Cancer and Oncology
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URN: urn:nbn:se:uu:diva-349356DOI: 10.1093/nar/gkx1190ISI: 000425294400020PubMedID: 29186616OAI: oai:DiVA.org:uu-349356DiVA, id: diva2:1202904
Funder
Swedish Cancer Society, 09 0773, 10 0452, 2016/445Swedish Research Council, 2015-02757Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-05-02Bibliographically approved

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Sundqvist, AndersVasilaki, EleftheriaHeldin, Carl-Henrik

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