**5.5.2 IL-6 and IL-8 expression**

IL-6 is a multifunctional cytokine that is involved in many different biological process, including immunological and inflammatory processes, tumor growth and angiogenesis (Hirano, Akira et al. 1990; Mateo, Reichner et al. 1994). IL-8 is another important cytokine that acts as a pro-angiogenic factor. Both of these cytokines can be induced by hypoxia (Yan, Tritto et al. 1995; Mizukami, Jo et al. 2005) and have been shown to upregulate VEGF mRNA expression (Cohen, Nahari et al. 1996). Studies indicate that active Rho proteins upregulate the expression of NFκB components in NIH-3T3 cells (Perona, Montaner et al. 1997; Montaner, Perona et al. 1998). Consistent with Rho-mediated activation of NFκB, HKG-CoA reductase inhibitors had been reported to reduce IL-6 expression by inhibiting Rho proteins (Ito, Ikeda et al. 2002). Rac1 has been shown to mediate the activation of a potential oncogen, STAT3, through NFκB regulated IL-6 signaling (Faruqi, Gomez et al. 2001).

IL-8 expression has also been found to be regulated by Rho proteins. In human endothelial cells, it has been shown that inhibition of RhoA, Rac1 and Cdc42 decreases NFκB activation and, therefore, decreases IL-8 mRNA and IL-8 protein expression (Hippenstiel, Soeth et al. 2000; Warny, Keates et al. 2000). In addition, RhoC has been shown to increase IL-6 and IL-8 expression in aggressive breast cancer cell lines (Xue, Bi et al. 2004). These evidences suggest that different Rho proteins modulate IL-6 and IL-8 through distinct signaling pathways.

Rho GTPases and Breast Cancer 575

(Watnick, Cheng et al. 2003). And the suppression of Tsp-1 always correlates with

It is apparent that individual members of Rho GTPases play specific roles in different aspects in breast cancer development (Fig. 4). Aberrant expression and activity of Rho proteins contribute to the transformation from normal epithelial phenotype, increases in proliferation, the promotion of angiogenesis, elevated motility, and metastasis to distant organs. RhoA, RhoC and Rac1 are frequently overexpressed in metastatic breast cancers. Manipulating the Rho GTPases' regulatory proteins and their effectors can induce activation of Rho proteins, , leading to aberrant transcription factor activation, including that of NFκB, that contribute to invasive phenotypes. All this evidence suggests that Rho GTPases could be targets in cancer therapy. Therefore, better knowledge of the the regulation mechanisms of Rho GTPases in breast cancer may be critical for a more in-depth understanding of tumor

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**6. Conclusion** 

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