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CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer
Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden;Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland.
Karolinska Inst, Inst Environm Med, Stockholm, Sweden;Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA.
Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
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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 hyperactivation of AKT and sensitized cells to TGF beta 1-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.

Significance: The tight junction protein CXADR controls epithelial-mesenchymal plasticity in breast cancer by stabilizing the AKT regulators PTEN and PHLPP2.

Place, publisher, year, edition, pages
2019. Vol. 79, no 1, p. 47-60
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-374436DOI: 10.1158/0008-5472.CAN-18-1742ISI: 000454833400006PubMedID: 30385615OAI: oai:DiVA.org:uu-374436DiVA, id: diva2:1282743
Funder
Swedish Research Council, 2017-03056Swedish Research Council, 2018-3114Swedish Cancer Society, CAN 2015/773Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-01-25Bibliographically approved

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