**3. Cancer-associated inflammation**

Although highly characterized for their protective capacity against infection, inflammatory leukocytes also reside within the tumor microenvironment. In fact, various immune cells are capable of eliminating transformed cells and thus preventing tumorigenesis in a process termed immunosurveillance (Dunn *et al.*, 2004). Whereas acute inflammation may prevent tumorigenesis by promoting an immune response directed against transformed cells, chronic inflammation promotes tumorigenesis. Rudolf Virchow is credited with making the seminal link between chronic inflammation and cancer by noting that human tumor biopsies were often infiltrated with inflammatory cells (Balkwill and Mantovani, 2001). Leukocytes can be detected in non-malignant tumors and carcinomas, including breast cancer (DeNardo and Coussens, 2007), which suggests an ongoing antitumor immune response. Despite the infiltration of leukocytes such as cytotoxic T-cells and NK-cells, the persistence of a tumor demonstrates immune evasion and highlights the local and systemic immune suppressive state of the tumor microenvironment and the tumor-bearing host, respectively.

Interleukin-6 in the Breast Tumor Microenvironment 169

STAT3 where it forms a complex with NF-κB to activate a subset of NF-κB target genes

Alternatively, IL-6 *trans*-signaling describes an IL-6 signaling pathway whereby an IL-6 soluble receptor (IL-6sR) binds IL-6 and subsequently ligates gp130 to stimulate STAT3 activation in cells that only express gp130. IL-6sR is naturally produced by either proteolytic cleavage of the membrane-bound IL-6R or alternative splicing of IL-6R mRNA (Rose-John *et al.*, 2006). Whereas IL-6 serum levels continue to increase with age, levels of serum IL-6sR rise until approximately age 70 at which time they gradually decline (Giuliani *et al.*, 2001). Furthermore, IL-6sR expression has been demonstrated in human breast cancer cell lines (Crichton *et al.*, 1996; Oh *et al.*, 1996; Singh *et al.*, 1995), suggesting that IL-6 *trans*-signaling mediates the effects of IL-6 in breast cancer cells. In contrast, an endogenous soluble gp130 (sgp130) specifically antagonizes IL-6 *trans*-signaling by exclusively ligating the IL-6/IL-6sR complex, thus having no effect on cells that express the membrane-bound IL-6R (Rose-John

(Yang and Stark, 2008).

*et al.*, 2006) (Figure 1).

Fig. 1. The IL-6/STAT3 signaling pathway

**5. Excessive IL-6 in human breast cancer** 

Aberrantly elevated IL-6 is associated with a poor prognosis in breast cancer (Bachelot *et al.*, 2003; Salgado *et al.*, 2003; Zhang and Adachi, 1999). Human breast tumors produce more IL-6 when compared to matched healthy breast tissue, and tumor IL-6 levels concurrently increase with tumor grade. In addition, increased serum IL-6 has been demonstrated in
