Multifaceted Roles of Interleukin-6 in Adipocyte-Breast Cancer Cell Interaction

Abstract

Breast cancer is the most common malignancy in women worldwide, with a developmental process spanning decades. The malignant cells recruit a variety of cells including fibroblasts, endothelial cells, immune cells, and adipocytes, creating the tumor microenvironment. The tumor microenvironment has emerged as active participants in breast cancer progression and response to treatment through autocrine and paracrine interaction with the malignant cells. Adipose tissue is abundant in the breast cancer microenvironment; interactions with cancer cells create cancer-associated adipocytes which produce a variety of adipokines that influence breast cancer initiation, metastasis, angiogenesis, and cachexia. Interleukin (IL)-6 has emerged as key compound significantly produced by breast cancer cells and adipocytes, with the potential of inducing proliferation, epithelial-mesenchymal phenotype, stem cell phenotype, angiogenesis, cachexia, and therapeutic resistance in breast cancer cells. Our aim is to present a brief knowledge of IL-6's role in breast cancer. This review summarizes our current understanding of the breast microenvironment, with emphasis on adipocytes as key players in breast cancer tumorigenesis. The effects of key adipocytes such as leptin, adipokines, TGF-b, and IL-6 are discussed. Finally, we discuss the role of IL-6 in various aspects of cancer progression.

Figure 1

Signaling pathway of IL-6. IL-6 secreted by cancer-associated adipocytes binds to the IL-6 receptor [1] on breast cancer cell and induces a cascade of JAK phosphorylation [2] that results in phosphorylation and activation of Stat3 [3]. Activated stat3 dimerizes with other phosphorylated stat3 [4], translocates into the nucleus, binds to target DNA sequences, and activates the transcription of genes under its control [5], which are usually involved with invasion, proliferation, metastasis, stemness, angiogenesis, immune suppression, and drug resistance. SHP1/SHP2, PIAS, and SOCs are negative feedback regulated of the JAK/STAT pathway [[6], [10], [11]]. The tumor cells also secrete IL-6 and other inflammatory molecules [8] that stimulate WAT browning [9] with increase in UCP1 expression, mitochondria, and thermogenesis. CNTO-328 and tocilizumab are monoclonal antibodies that target and inhibit IL-6 activation of the JAK/Stat3 signaling [7].