**10. References**

144 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

due to the presence of an altered TA-ECM, an integrin-dependent activation of Src family kinases results in the increase of NF-B activity which blocks the production of certain microRNAs such as Let-7. Under these conditions, IL-6 production is promoted resulting in the increased secretion of this pro-tumorigenic cytokine, which in turn induces or promotes a positive feedback in tumor cells (Iliopoulos et al., 2009). Moreover, activated myofibroblastic and cancer cells are known to remodel the stromal ECM by means of increased secretion of MMPs and urokinase-type plasminogen activator (uPA). These enzymes cleave the ECM molecules to release fragments that contain chemotactic properties called matrikines that activate leukocytes to also release inflammatory cytokines (Maquart et al., 2004; Silzle et al., 2004). For example, a special feature of MMP-2, -3 and -9 is that these proteases can increase the availability of IL-1b at the tumor microenvironment by cleavage of the pIL-1b (immature IL-1b) (Schonbeck et al., 1998). Also, analyses of co-cultures containing both breast cancer cells and CAFs have shown increases in stromal MMP-2 and MMP-9 expression (Singer et al., 2002). These observations concur with observations stemming from an immunohistochemical study where tissue arrays of breast cancer patients showed that intratumor stromal fibroblasts express MMP-2, -7, and -14, while fibroblast at the invasive front highly express MMP-9. What is more, this specific profile of stromal MMPs staining was found to be a predictor of future distant metastases occurrences (Del Casar et al., 2009). Another uncovered effect of released MMPs into the tumor stroma is the capacity of these molecules to promote a permissive environment that supports epithelial tumorigenic progression including the promotion of genomic alterations (Radisky, E.S. & Radisky, 2007). In the mammary glands of transgenic mice, the overexpression of MMP-3 has been shown to be sufficient to stimulate myofibroblastic presence, increased fibrosis, epithelial hyperplasia, and development of mammary carcinoma (Thomasset et al., 1998). What is more, mammary epithelial cells exposed to stromal MMP-3 showed activation of a genotoxic metabolic pathway, where the over expression of the spliced variant Rac1b produced DNA-damaging superoxide radicals and induced EMT (Radisky, D.C. et al., 2005). Interestingly, the epithelial genomic alterations induced by stromal MMPs *in vitro,* suggest a possible mechanism to understand the presence of areas with genomic imbalance patterns detected in histologically normal tissues adjacent to the tumor stroma (Ellsworth et

al., 2004; Holliday et al., 2009).

**8. Targeting fibroblasts as an anti-cancer therapy** 

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**8** 

*USA* 

**Interleukin-6 in the Breast** 

**Tumor Microenvironment** 

*The Ohio State University, Columbus, Ohio* 

Greater than 200,000 new cases of breast cancer cases were diagnosed in 2010 in the United States, with approximately 40,000 women succumbing to the disease (www.cancer.gov). Globally, an estimated 1.38 million new cases of breast cancer were diagnosed in 2008, with greater than 450,000 women succumbing to the disease (Jemal *et al.*, 2011). Despite our improved understanding of breast carcinogenesis, breast cancer remains the second most commonly diagnosed cancer in women behind non-melanoma skin cancer and the second leading cause of death in women behind lung cancer. These epidemiological statistics highlight the overwhelming clinical dilemma of breast cancer and emphasize the need for novel therapeutic targets and prevention strategies. Countless studies in the fields of mammary gland development and breast cancer have led to an appreciation of a breast tumor microenvironment that actively contributes to the heterogeneous nature of breast cancer. The current review will focus on the impact of IL-6 and STAT3 activation in the breast tumor microenvironment and subsequently present rationale for targeting the IL-6/STAT3 signaling pathway in this setting. IL-6 is a quintessential pleiotropic cytokine produced by a diverse number of cell populations, most of which can localize to the breast tumor microenvironment. Excessive IL-6 has been demonstrated in primary breast tumors and breast cancer patient sera and is associated with poor clinical outcomes in breast cancer. These clinical associations are corroborated by emerging preclinical data revealing that IL-6 is a potent growth factor and promotes an epithelial-mesenchymal (EMT) phenotype in breast cancer cells to indicate that IL-6 in the breast tumor microenvironment is clinically relevant. Numerous clinical reports have now demonstrated the safety and efficacy of IL-6 signaling antagonists in multiple diseases, which supports future investigations of these

Estrogen receptor-alpha (ERα) is a latent cytoplasmic ligand-activated transcription factor utilized by clinicians to subclassify the heterogeneous disease of breast cancer. ERα-positive breast cancer incidence increases up to age 51, the mean age of menopause, and continues to increase until age 80. Conversely, ERα-negative breast cancer incidence plateaus and even slightly decreases at age 51, while demonstrating an increase prior to age 50 comparable to that of ERα-positive disease. This discrepancy between the two incidence rates at menopause produces an inflection in the incidence rate of all breast cancer cases which has been termed Clemmesen's hook (Anderson and Matsuno, 2006). Whereas the prevalence of

**1. Introduction** 

therapies in breast cancer.

Nicholas J. Sullivan

