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

Sara G Manore,Daniel L Doheny,Hui-Wen Lo,Grace L Wong

doi:10.3389/fonc.2022.866014

Sara G Manore, Daniel L Doheny + Show 2 more

Open Access

https://doi.org/10.3389/fonc.2022.866014

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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.

Highlights

Breast cancer affects 1 in 8 women in the United States and is the second leading cause of cancerrelated deaths in women behind lung cancer [1]
Since IL-6Ra and gp130 are required for signal transduction, the previous contradictory results may have been attributed to a lack of receptor expression in tested breast cancer cell lines, or that IL-6’s pleiotropic effects may depend on Janus kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3) pathway activation
It remains pertinent to maintain a homeostatic balance of IL-6/JAK/STAT3 as dysregulation creates a vicious autocrine and paracrine inflammatory loop which promotes breast cancer metastasis and therapeutic resistance

Summary

Introduction

Breast cancer affects 1 in 8 women in the United States and is the second leading cause of cancerrelated deaths in women behind lung cancer [1]. IL-6 expression correlates with poor patient survival, promotes growth and invasion, and mediates metastatic progression, which identifies the IL-6 signaling axis as a potential therapeutic target [25, 26]. Since IL-6Ra and gp130 are required for signal transduction, the previous contradictory results may have been attributed to a lack of receptor expression in tested breast cancer cell lines, or that IL-6’s pleiotropic effects may depend on JAK/STAT3 pathway activation.

Results

Conclusion