Recent advances reveal IL-8 signaling as a potential key to targeting breast cancer stem cells

Abstract

Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are purported to be responsible for tumor initiation, maintenance, metastases, and disease recurrence. Interleukin-8 (IL-8) is upregulated in breast cancer compared with normal breast tissue and is associated with poor prognosis. IL-8 is reported to promote breast cancer progression by increasing cell invasion, angiogenesis, and metastases and is upregulated in HER2-positive cancers. Recently, we and others have established that IL-8 via its cognate receptors, CXCR1 and CXCR2, is also involved in regulating breast CSC activity. Our work demonstrates that in metastatic breast CSCs, CXCR1/2 signals via transactivation of HER2. Given the importance of HER2 in breast cancer and in regulating CSC activity, a pathway driving the activation of these receptors would have important biological and clinical consequences, especially in tumors that express high levels of IL-8 and other CXCR1/2-activating ligands. Here, we review the IL-8 signaling pathway and the role of HER2 in maintaining an IL-8 inflammatory loop and discuss the potential of combining CXCR1/2 inhibitors with other treatments such as HER2-targeted therapy as a novel approach to eliminate CSCs and improve patient survival.

Figure 1

Model of cytokine networks depicting the proposed interactions between breast cancer cells and stromal cells. (a) Interleukin-8 (IL-8) is secreted by cancer cells, mesenchymal cells, and macrophages via multiple signaling pathways. (b) IL-8 promotes breast cancer stem-like cell (CSC) activity via CXCR1/2 by activating EGFR/HER2-dependent and -independent signaling pathways. Red circles denote CXCR1/2 ligands: IL-8/CXCL8, CXCL1/GRO-α, CXCL5, CXCL6/GCP-2, and CXCL7/NAP-2. bFGF, basic fibroblast growth factor; CXCL, C-X-C motif ligand; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GCP-2, granulocyte chemotactic protein-2; GRO, growth-regulated oncogene; HER2, human growth factor receptor 2; IGF-1R, insulin-like growth factor 1 receptor; JAK/STAT, Janus kinase/signal transducers and activators of transcription; NAP-2, neutrophil-activating protein-2; Src, sarcoma kinase; TGF-β, transforming growth factor-beta.