**8. Therapeutic targeting of the IL-6/STAT3 pathway**

IL-6 levels are increased in human breast tumors and breast cancer patient sera, and excessive IL-6, both circulating and within the breast tumor microenvironment, is associated with poor clinical outcomes in breast cancer. STAT3, a critical downstream mediator of IL-6 signaling, is constitutively activated in more than half of human cancers and promotes the expression of proliferative, anti-apoptotic, immune suppressive, and pro-angiogenic target genes, which all potentiate carcinogenesis. Whereas the IL-6 signaling network has been targeted in numerous autoimmune diseases and cancers, this therapeutic strategy has yet to be clinically employed for breast cancer. Increased preclinical reports have revealed novel

Interleukin-6 in the Breast Tumor Microenvironment 175

Fig. 2. Breast cancer cell ERα status dictates paracrine vs. autocrine IL-6 utilization.

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545.

mechanisms underlying IL-6/STAT3 signaling in breast cancer cells such as enhanced growth, induction of EMT, multidrug resistance, and recruitment of peripheral fibroblasts. Taken together, accumulating preclinical and clinical data emphasize IL-6 as a highly attractive therapeutic target in breast cancer. It is therefore imperative that more work be done to evaluate current therapeutics and develop novel agents that target IL-6/STAT3 signaling in breast cancer models.

Multiple strategies could be utilized to target the IL-6/STAT3 pathway, but first and most obvious would be anti-IL-6 neutralizing antibodies. One such anti-IL-6 monoclonal antibody is Siltuximab (CNTO 328). The safety and efficacy of Situximab has been demonstrated in preclinical studies and phase I/II clinical trials of diverse human pathologies and malignancies including Castleman's disease (van Rhee *et al.*, 2010), multiple myeloma (Hunsucker *et al.*, 2011; Voorhees *et al.*, 2007), prostate cancer (Cavarretta *et al.*, 2007; Cavarretta *et al.*, 2008; Dorff *et al.*, 2010; Karkera *et al.*, 2011), renal cell carcinoma (Puchalski *et al.*, 2010; Rossi *et al.*, 2010), non-small cell lung cancer (Song *et al.*, 2010), and ovarian cancer (Guo *et al.*, 2010). Furthermore, IL-6R can be targeted with tocilizumab, an anti-IL-6R monoclonal antibody that has shown promising results in IL-6 driven autoimmune diseases (Tanaka et al., 2011) and was recently approved by the FDA for the treatment of rheumatoid arthritis. The promiscuous IL-6 coreceptor, gp130, also has an endogenous soluble form (sgp130) that exclusively inhibits IL-6 *trans*-signaling, thus preserving classical IL-6 signaling. Therapeutic sgp130 would potentially be more targeted toward breast cancer cells, which generally lack membrane-associated IL-6R and therefore utilize IL-6 trans-signaling through IL-6sR. Recombinant soluble gp130 (sgp130- Fc) has been shown to inhibit murine colon carcinogenesis (Becker *et al.*, 2004), suggesting that it may prove effective in breast cancer as well. Finally, a growing number of nonselective kinase inhibitors and recent focus on specific JAK and STAT3 inhibitor development will provide further insight into the roles of JAK and STAT3 in breast cancer.
