STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential

Simple Summary Many signaling pathways are overactive in breast cancer, and among them is the STAT3 signaling pathway. STAT3 is activated by secreted factors within the breast tumor, many of which are elevated and correlate to advanced disease and poor survival outcomes. This review examines how STAT3 signaling is activated in breast cancer by the proinflammatory, gp130 cytokines, interleukins 6 and 11. We evaluate how this signaling cascade functions in the various cells of the tumor microenvironment to drive disease progression and metastasis. We discuss how our understanding of these processes may lead to the development of novel therapeutics to tackle advanced disease. 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.

Automated summary

This review explores the role of the STAT3 signaling pathway in breast cancer and its correlation with disease progression and metastasis. The study discusses the function of this signaling cascade in the tumor microenvironment, as well as the contribution of IL-6 family cytokines to cancer and potential therapeutic targets.