Key Factor Regulating Inflammatory Microenvironment, Metastasis, and Resistance in Breast Cancer: Interleukin-1 Signaling

Abstract

Breast cancer is one of the top-ranked cancers for incidence and mortality worldwide. The biggest challenges in breast cancer treatment are metastasis and drug resistance, for which work on molecular evaluation, mechanism studies, and screening of therapeutic targets is ongoing. Factors that lead to inflammatory infiltration and immune system suppression in the tumor microenvironment are potential therapeutic targets. Interleukin-1 is known as a proinflammatory and immunostimulatory cytokine, which plays important roles in inflammatory diseases. Recent studies have shown that interleukin-1 cytokines drive the formation and maintenance of an inflammatory/immunosuppressive microenvironment through complex intercellular signal crosstalk and tight intracellular signal transduction, which were found to be potentially involved in the mechanism of metastasis and drug resistance of breast cancer. Some preclinical and clinical treatments or interventions to block the interleukin-1/interleukin-1 receptor system and its up- and downstream signaling cascades have also been proven effective. This study provides an overview of IL-1-mediated signal communication in breast cancer and discusses the potential of IL-1 as a therapeutic target especially for metastatic breast cancer and combination therapy and current problems, aiming at enlightening new ideas in the study of inflammatory cytokines and immune networks in the tumor microenvironment.

Figure 1

Typical IL-1 signaling. (a) Synthesis and secretion of IL-1α and IL-1β. (b) Several natural or recombinant biologics block IL-1 and its process of binding to membrane receptors. (c) IL-1 activated intracellular signaling. Abbreviations: IL—interleukin; IL-1R—IL-1 receptor; IL-1Ra—IL-1 receptor antagonist; IL-1RAcP—IL-1 receptor accessory protein; Ig—immunoglobulin; TIR—Toll- and IL-1R-like; NLRP3—NOD-like receptor family PYD domain-containing protein 3; ASC—apoptosis-associated speck-like protein; MyD88—myeloid differentiation primary response gene 88; IRAK—interleukin-1 receptor-associated kinase; TRAF6—TNF receptor-associated factor 6; MKK—mitogen-activated protein kinase kinase; JNK—c-Jun N-terminal kinase; ERK—extracellular signal-regulated kinase; MAPK—mitogen-activated protein kinase; IKB—inhibitor kappa B; IKK—inhibitor kappa B kinase; NF-κB—nuclear factor kappa B; AP1—activator protein-1.

Figure 2

IL-1 signaling-mediated intercellular and intracellular crosstalk in a breast cancer microenvironment. Blue arrows indicate the source and fate of IL-1. Yellow arrows indicate the network of reciprocal influences among different cytokines engaged by IL-1. The source of IL-1 in the breast cancer microenvironment is extensive. Its directions mainly include various immune or inflammatory cells, where it acts to recruit cells and promote differentiation and secretion. Abbreviations: IL—interleukin; MMP—matrix metalloproteinase; TSLP—thymic stromal lymphopoietin; TGF-β—transforming growth factor-beta; TNF-α—tumor necrosis factor-alpha; sCD4—soluble cluster determinant 4; OSM—oncostatin M; SCFs—stem cell factors; G-CSF—granulocyte-colony stimulating factor; VEGF—vascular endothelial growth factor; CXCL—(C-X-C motif) ligand; CCL—C-C chemokine ligand.

Figure 3

IL-1 signaling-mediated intracellular signal transduction and activation in a breast cancer microenvironment. Abbreviations: IL—interleukin; IL-1R—IL-1 receptor; IL-1Ra—IL-1 receptor antagonist; HER2—human epidermal growth factor receptor 2; ERα—estrogen receptor alpha; PI3K—phosphoinositide 3-kinase; mTOR—mammalian/mechanistic target of rapamycin; NF-κB—nuclear factor kappa B; STAT3—signal transducer and activator of transcription 3; AhR—hydrocarbon receptor; RORγt—retinoid-related orphan nuclear receptor gamma t; CD4—cluster determinant 4; JNK—c-Jun N-terminal kinase; CXCR3—C-X-C chemokine receptor type 3; ZEB1—zinc-finger E-box binding protein 1; HIF-1α—hypoxia-inducible transcription factor-1 alpha; Wnt—wingless and int-1; CREB—cyclic AMP response-element binding protein; TG2—transglutaminase 2; TRAF6—TNF receptor-associated factor 6; NLRP3—NOD-like receptor family PYD domain-containing protein 3; NLRC4—NOD-like receptor family CARD-containing protein 4.