Fig. 2
From: The role of TGF-β and its crosstalk with RAC1/RAC1b signaling in breast and pancreas carcinoma
The dual role of TGF-β in tumor progression and its association with RAC1b and RAC1 expression. Depending on the stage of cancer progression, TGF-β can act either as tumor suppressor (left panel) or tumor promoter (right panel) by inhibiting or enhancing, respectively, cell migration, invasion, and metastasis, through the Smad signaling pathway. This phenomenon is known as the “TGF-β paradox”. Early-stage tumors with high RAC1b or a high RAC1b:RAC1 ratio are less invasive and metastatic due to functional inhibition of RAC1 (left-hand side), while advanced tumors expressing little RAC1b or maintaining a low RAC1b:RAC1 ratio eventually become more invasive and metastatic due to a preponderance of tumor-promoting RAC1 (right-hand side). Hence, the relative expression and activity of RAC1b and RAC1 may ultimately determine the tumor cells’ response to TGF-β during tumor progression. It should be noted that the tumor-suppressive effect of Rac1b is specific for TGF-β since in response to other EMT-inducers, such as MMP3, Rac1b can increase malignant transformation [92]. The red arrow indicates inhibition and the green arrow activation of SMAD2 and SMAD3 (SMAD2/3) activity