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.
Highlights
Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices
MCT-1 is a poor-prognosis marker of aggressive breast cancer Oncogenic MCT-1 activation in breast cancer was investigated using the Kaplan-Meier Plotter database [24], and we observed that high MCT-1 expression in patients was associated with lower overall survival (OS) in overall breast cancer (p = 0.0053) as well as in TP53 wild type (p = 0.024) (Additional file 1: Figure S1A), lymph node metastasis-free (p = 0.001), HER2-negative (p = 0.0067), luminal-A (p = 0.026) and luminal-B (p = 0.043) breast cancers than that of patients with low-level MCT-1
We found that MCT-1 increased the programmed death-ligand 1 (PD-L1), IL-6 and IL-6 receptor (IL-6R) amounts (Fig. 2e), and IL-6 further advanced MCT-1-induced EGFR and signal transducer and activator of transcription 3 (Stat3) phospho-activation as well as Snail, Slug, ZEB1 and N-cadherin but further suppressed E-cadherin in a dose-dependent manner
Summary
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. IL-6/IL-6R/gp130 pathway communicates between breast tumor and immune cells [10], resulting in tumor promotion and enriched effect on BCSCs. targeting IL-6/Sta signaling axis potentially improve the efficacy of cancer immunotherapy [11]. The use of nanoparticlebased system for CD44 and IL-6R immunotherapy suppresses Stat, Sox, VEGF-A, MMP-9 and CD206 expression in breast tissues as well as Sox2+/CD206+ stem cells in lung metastatic foci
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