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

Abstract

BackgroundTriple-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.ResultsWe 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.ConclusionsThe MCT-1 pathway is a novel and promising therapeutic target for TNBC.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0988-0) contains supplementary material, which is available to authorized users.

CD155 contributes to the mesenchymal phenotype of triple‐negative breast cancer

“…The IL‐6/Stat3 pathway was identified to cross‐talk with CD155 in TNBC cells. IL‐6 was involved in TNBC cell growth, survival, migration, metastasis and stemness . As a downstream intracellular molecule of IL‐6, Stat3 was also overactivated in TNBC, and associated with the aggressive phenotype .…”

Circular RNA hsa_circ_0000654 promotes esophageal squamous cell carcinoma progression by regulating the miR‐149‐5p/IL‐6/STAT3 pathway

“…Then, the STAT 3 complex is transferred from the cytoplasm to the nucleus, binds to a consistent DNA element, and initiates transcription of STAT 3 target genes, including cyclinD 1, Bcl‐XL, c‐myc, MCL 1, and VEGF . Additionally, IL‐6 is modulated by multiple miRNAs, for instance, miR‐34a negatively modulates IL‐6 in breast cancer to exert a tumor suppressor effect . miR‐608 binds to the 3′UTR of IL‐6 to inhibit ESCC progression .…”

“…22,24 Additionally, IL-6 is modulated by multiple miRNAs, for instance, miR-34a negatively modulates IL-6 in breast cancer to exert a tumor suppressor effect. 43 miR-608 binds to the 3 0 UTR of IL-6 to inhibit ESCC progression. 42 We demonstrated that circ_0000654 enhanced IL-6/STAT3 expression in ESCC cells, and activation of IL-6/STAT3 in ESCC cells partially reversed the effect of circ_0000654 or attenuated the tumorsuppressive function of miR-149-5p.…”

Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple‐negative breast cancer

“…In addition, accumulating evidence suggests that the density of stroma‐infiltrating immune cells reflects the focal immune response of patients to chemotherapy regimens and may serve as a promising predictor 11‐13 . Although some studies have investigated the prognostic relevance of some immune cells in TNBC, there are few systematic studies on the association between the overall stromal immune cell signature and clinical outcomes 12,14,15 …”