**6. Conclusion**

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

FGF1 and FGF2 are the two earliest characterized members of the FGF family of growth factors. FGF is an angiogenic factor that is frequently overexpressed in breast and prostate cancers. Rac1 and Cdc42 have been reported to increase FGF1 expression by stimulating the FGF1 gene promoter region (Chotani, Touhalisky et al. 2000). One study demonstrated that Rac1 activity is required for FGF2-induced activation of Ras/MAPK signaling in human breast cell line MCF7 (Liu, Chevet et al. 1999). In addition, medium collected from RhoC stably transfected HME and SUM149 cells present higher level of FGF2, in comparison to those collected from control transfected HME cells (van Golen, Wu et al. 2000). However,

Fig. 4. Rho family GTPases are involved in different stages of breast cancer progression: dedifferentiation and upregulation of uncontrolled proliferation, angiogenesis, invasion and

The anti-angiogenic molecule Tsp-1 is capable of inhibiting metalloproteinase-9 (MMP9) from releasing the VEGF sequestered in ECM. The oncoprotein Ras has been reported to increase VEGF expression and inhibit Tsp-1 expression. One study showed that the inhibitory function of Ras on Tsp-1 via PI3K pathway also involve RhoA and RhoC in human embryonic kidney cell lines, human mammary cell lines, and breast cancer cell lines

how Rho proteins regulate FGF expression remains unclear.

**5.5.3 FGF activation** 

metastasis.

**5.5.4 Repression of Tsp-1** 

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 biology, facilitating development of novel approaches for cancer treatment.
