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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/11838


    Title: MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer
    Authors: Weng, YS;Tseng, HY;Chen, YA;Shen, PC;Al Haq, AT;Chen, LM;Tung, YC;Hsu, HL
    Contributors: Institute of Molecular and Genomic Medicine
    Abstract: BACKGROUND: Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices. Cytokine networking between cancer cells and the tumor microenvironment (TME) maintains the self-renewing subpopulation of breast cancer stem cells (BCSCs) that mediate tumor heterogeneity, resistance and recurrence. Immunotherapy of those factors combined with targeted therapy or chemoagents may advantage TNBC treatment. RESULTS: We found that the oncogene Multiple Copies in T-cell Malignancy 1 (MCT-1/MCTS1) expression is a new poor-prognosis marker in patients with aggressive breast cancers. Overexpressing MCT-1 perturbed the oncogenic breast epithelial acini morphogenesis and stimulated epithelial-mesenchymal transition and matrix metalloproteinase activation in invasive TNBC cells, which were repressed after MCT-1 gene silencing. As mammary tumor progression was promoted by oncogenic MCT-1 activation, tumor-promoting M2 macrophages were enriched in TME, whereas M2 macrophages were decreased and tumor-suppressive M1 macrophages were increased as the tumor was repressed via MCT-1 knockdown. MCT-1 stimulated interleukin-6 (IL-6) secretion that promoted monocytic THP-1 polarization into M2-like macrophages to increase TNBC cell invasiveness. In addition, MCT-1 elevated the soluble IL-6 receptor levels, and thus, IL-6R antibodies antagonized the effect of MCT-1 on promoting M2-like polarization and cancer cell invasion. Notably, MCT-1 increased the features of BCSCs, which were further advanced by IL-6 but prevented by tocilizumab, a humanized IL-6R antibody, thus MCT-1 knockdown and tocilizumab synergistically inhibited TNBC stemness. Tumor suppressor miR-34a was induced upon MCT-1 knockdown that inhibited IL-6R expression and activated M1 polarization. CONCLUSIONS: The MCT-1 pathway is a novel and promising therapeutic target for TNBC.
    Date: 2019-03-18
    Relation: Molecular Cancer. 2019 Mar 18(1);18:Article number 42.
    Link to: http://dx.doi.org/10.1186/s12943-019-0988-0
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1476-4598&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000461954900001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85063165164
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