IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment

Abstract

Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.

Pan-cancer analyses confirmed the cuproptosis-related gene FDX1 as an immunotherapy predictor and prognostic biomarker

“…This was consistent with existing tumor mechanisms (Li et al, 2011;Currie et al, 2013;Gonzalez and Medici, 2014;Ashton et al, 2018). Among them, we paid special attention to multiple immune pathways, including the inflammatory response, interferon gamma response, TNF-a signaling pathway and IL-6/JAK/ STAT3 signaling, all of which had been shown to be closely related to tumor development (Balkwill, 2009;Diakos et al, 2014;Alspach et al, 2019;Manore et al, 2022). To further investigate the potential value of FDX1, we explored the correlation of FDX1 with the tumor microenvironment and immune cell infiltration.…”

Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer

“…Interestingly, increased IL6 was correlated with poor prognosis, progression, and migration of ER-positive breast cancer [ 129 ]. IL6 was shown in vitro to activate the signal transducer and activator of transcription 3 (STAT3)/protein kinase B (AKT)/mitogen-activated protein kinase (MAPK) pathways, triggering proliferation of both triple negative and triple positive breast cancer cell lines [ 103 , 104 , 130 ]. TNFα, another important inflammatory cytokine released by adipose stromal cells, including ASCs/MSCs, was increased in the TME of patients with obesity, causing adipose tissue inflammation and inhibiting apoptosis of TNBC cells [ 131 , 132 ].…”

Chronic inflammation, cancer development and immunotherapy

“…Importantly, the growthenhancing effects of IL-6 on cancer cells also extend to cancer stem cells, capable of self-renewal and expansion, which require STAT3 to act synergistically with stem cell transcription factors such as NANOG (Codd et al, 2018). These interactions ultimately lead to multidrug resistance and progression of multiple tumors, including lung, bladder, breast, ovarian, colorectal and hematological malignancies (Liu et al, 2015;Wei 2019;Manore et al, 2022).…”