MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer

• Published in: Molecular cancer Vol. 18; no. 1; p. 42
• Main Authors: Weng, Yueh-Shan, Tseng, Hong-Yu, Chen, Yen-An, Shen, Pei-Chun, Al Haq, Aushia Tanzih, Chen, Li-Mei, Tung, Yi-Chung, Hsu, Hsin-Ling
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.03.2019; BioMed Central; BMC
• Subjects: Animals; Antibodies; Apoptosis; Biomarkers, Tumor; Breast cancer; Cancer cells; Cancer patients; Cancer stemness; Case-Control Studies; Cell activation; Cell adhesion & migration; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation; Cytokines; Development and progression; EMT; Epithelial-Mesenchymal Transition; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Gene silencing; Genes; Genetic aspects; Health aspects; Heterogeneity; Humans; Immunotherapy; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukins; Invasiveness; Leukemia; Lymphatic system; Lymphocytes T; M2 macrophages; Macrophages; Macrophages - metabolism; Macrophages - pathology; Malignancy; Mammary gland; Matrix metalloproteinase; MCT-1/miR-34a/IL-6/IL-6R pathway; Medical prognosis; Mesenchyme; Metalloproteinase; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; MicroRNAs - genetics; Monocytes; Morphogenesis; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Ovarian cancer; Polarization; Prognosis; Prostate; Proteins; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Recurrence (Disease); Signal Transduction; Stem cells; T cells; Therapeutic applications; Tocilizumab; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Cells, Cultured; Tumor necrosis factor-TNF; Tumor suppressor genes; Tumors; Xenograft Model Antitumor Assays; M2 macrophages; Cancer stemness; MCT-1/miR-34a/IL-6/IL-6R pathway; EMT
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-019-0988-0

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. 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. The MCT-1 pathway is a novel and promising therapeutic target for TNBC.