Tamoxifen and AEBS ligands induced apoptosis and autophagy in breast cancer cells through the stimulation of sterol accumulation

Abstract

Tamoxifen (Tx) interacts with high affinity to the microsomal antiestrogen binding site (AEBS) which is a hetero-oligomeric complex involved in cholesterol metabolism. We established that Tx and other AEBS ligands induce breast cancer cell differentiation, apoptosis and autophagy through the induction of sterol accumulation. We determined that cell death is sterol- and ROS-dependent and is prevented by the antioxidant vitamin E. Macroautophagy is characterized by the accumulation of autophagic vacuoles, an increase in the expression of Beclin 1 and the stimulation of autophagic flux. We established that macroautophagy is sterol-dependent and is associated with cell survival rather than cytotoxicity, since blockage of macroautophagy sensitizes cells to AEBS ligands. These results show that the accumulation of sterols by AEBS ligands in MCF-7 cells induces both apoptosis and macroautophagy. Collectively, these data support a therapeutic potential for selective AEBS ligands in breast cancer management and reveal a mechanism that explains the induction of autophagy in MCF-7 cells by Tx and other selective estrogen receptor modulators. Moreover these data give pharmacological clues to improve the apoptotic efficacy of AEBS ligands.