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Cancer Res. 2019 Jan 1;79(1):47-60. doi: 10.1158/0008-5472.CAN-18-1742. Epub 2018 Nov 1.

CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.

Author information

1
Department of Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, Stockholm, Sweden.
2
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
3
Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
4
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
5
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.
6
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
7
Department of Surgical and Perioperative Sciences, Umea University, Umea, Sweden.
8
Department of Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, Stockholm, Sweden. jonas.fuxe@ki.se.
#
Contributed equally

Abstract

: 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 TGFβ1-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.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/1/47/F1.large.jpg.

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