STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential

Abstract

Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets.

IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells

“…In Peutz Jeghers syndrome, heterozygous loss-of-function in LKB1 is associated with high levels of IL11 in intestinal polyps and an increased risk of cancers ( Ollila et al., 2017 ). There is extensive literature on IL11-induced activation of JAK/STAT3 in cancer cells ( Ernst and Putoczki, 2014 ; To et al., 2022 ) and on the association of IL11 with chemotherapy resistance and cancer metastasis ( Ernst and Putoczki, 2014 ; Janiszewska et al., 2019 ; Marusyk et al., 2014 ). We suggest that IL11/ERK-mediated inactivation of LKB1/AMPK in cancer cells, which has been overlooked, underlies some of the effects of IL11 in oncogenesis, perhaps specifically cancers associated with SNAI1 expression ( Barrallo-Gimeno and Nieto, 2005 ; Su et al., 2020 ).…”

The EGFR Signaling Modulates in Mesenchymal Stem Cells the Expression of miRNAs Involved in the Interaction with Breast Cancer Cells

“…Among these, we identified as the candidate miR-23c target Interleukin 6 Receptor (IL-6R), whose ligand, IL-6, has been shown to play a pivotal role in breast cancer growth and metastasis. In addition, the increased expression of IL-6R correlated with disease progression and poor patient outcome in breast cancer [ 20 ]. To confirm that IL-6R is a target of miR-23c, we cloned the 3′-UTR of IL-6R (WT) or the corresponding mutant construct (MUT), containing a mutation in two of the three putative miR-23c binding sites, in a luciferase reporter plasmid ( Figure 6 A).…”

“…Following bioinformatics and functional experiments, we found that IL-6R is a target of miR-23c. IL-6R is involved in the IL-6/IL-6R/STAT3 signaling pathway, whose role in breast cancer progression has been extensively demonstrated [ 20 , 33 ]. In addition, STAT3 signaling contributes to cell proliferation, survival, migration and invasion of TNBC [ 34 , 35 ].…”

Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarisation through phosphorylation of STAT3

“…ROCK regulating the phosphorylation of STAT3 to promote macrophage polarisation is not a new concept, and has previously been reported in chronic graft versus host disease, hepatocellular carcinoma and breast cancer. 88 , 89 , 90 To investigate the mechanism by which ROCK regulates macrophage polarisation, we elevated the phosphorylation of STAT3 in bleomycin‐ and radiation‐induced PF cells treated with WXWH0265, a ROCK inhibitor. The phosphorylation of STAT3 was inhibited by the decrease in M2 macrophage polarisation after WXWH0265 treatment, which verified our hypothesis.…”