Autocrine TGF-β protects breast cancer cells from apoptosis through reduction of BH3-only protein, Bim

Cancer cells undergo multi-step processes in obtaining the ability to metastasize, and are constantly exposed to signals that induce apoptosis. Acquisition of anti-apoptotic properties by cancer cells is important for metastasis, and recent studies suggest that transforming growth factor (TGF)-beta promotes the survival of certain types of cancer cells. Here, we found that in highly metastatic breast cancer cells, JygMC(A), JygMC(B) and 4T1, TGF-beta ligands were produced in autocrine fashion. Pharmacological inhibition of endogenous TGF-beta signalling by a TGF-beta type I receptor kinase inhibitor in serum-free conditions increased the expression of BH3-only protein, Bim (also known as Bcl2-like 11) in JygMC(A) and JygMC(B) cells, and caused apoptotic cell death. We also found that induction of Bim by TGF-beta was not observed in Foxc1 knocked-down cancer cells. These findings suggest that TGF-beta plays a crucial role in the regulation of survival of certain types of cancer cells through the TGF-beta-Foxc1-Bim pathway, and that specific inhibitors of TGF-beta signalling might be useful as apoptosis inducers in breast cancer cells.