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CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.
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2019 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 1, p. 47-60Article in journal (Refereed) Published
Abstract [en]

Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie- and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyper-activation of AKT and sensitized cells to TGF-β1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2019. Vol. 79, no 1, p. 47-60
National Category
Basic Medicine Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-154580DOI: 10.1158/0008-5472.CAN-18-1742ISI: 000454833400006PubMedID: 30385615OAI: oai:DiVA.org:umu-154580DiVA, id: diva2:1272799
Funder
Swedish Research Council, 2017-03056Swedish Research Council, 2018-3114Swedish Cancer Society, CAN 2015/773Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-01-25Bibliographically approved

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Sund, Malin

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