IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment

Abstract

The IL-6 cytokine family is a group of signaling molecules with wide expression and function across vertebrates. Each member of the family signals by binding to its specific receptor and at least one molecule of gp130, which is the common transmembrane receptor subunit for the whole group. Signal transduction upon stimulation of the receptor complex results in the activation of multiple downstream cascades, among which, in mammary cells, the JAK-STAT3 pathway plays a central role. In this review, we summarize the role of the IL-6 cytokine family-specifically IL-6 itself, LIF, OSM, and IL-11-as relevant players during breast cancer progression. We have compiled evidence indicating that this group of soluble factors may be used for early and more precise breast cancer diagnosis and to design targeted therapy to treat or even prevent metastasis development, particularly to the bone. Expression profiles and possible therapeutic use of their specific receptors in the different breast cancer subtypes are also described. In addition, participation of these cytokines in pathologies of the breast linked to lactation and involution of the gland, as post-partum breast cancer and mastitis, is discussed.

Keywords: IL-11; IL-6; LIF; OSM; breast cancer; mastitis; tumor microenvironment.

Figure 1

IL-6 cytokine pathway activation in breast cancer cells. IL-6 is secreted by tumor and stroma cells, such as cancer associated adipocytes (CAAs), cancer associated fibroblasts (CAFs), lymphatic endothelial cells (LECs), and myeloid derived stem cells (MDSCs). IL-6 binds to either transmembrane (mIL-6R) or soluble (sIL-6R) IL-6 receptor and to gp130 inducing ‘classic signaling’ through mIL-6R or ‘trans-signaling’ through sIL-6R (A). LIF binds to transmembrane LIF receptor (mLIFR) and gp130 inducing downstream signaling. LIF binding to soluble LIF receptors (sLIFR) blocks interaction with gp130 inhibiting LIF pathway activation (B). At the surface of target cells, secreted IL-6 cytokine family members bind to their specific receptors and gp130 to activate intracellular signaling cascades (C).