Fig. 3. A scheme showing the different mechanisms of tamoxifen resistance: (1) Loss of ERα expression and function lead to disappearance of the molecular target for tamoxifen (2) altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, (3) ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, (4) altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes such as CYP2D6, (5) regulation of autophagy and/or apoptosis,(6) ER-negative cancer stem cells that differentiate over growth inhibition of ER-positive cancer cells upon antiestrogen treatment, and(7) antioxidant protein-mediated cell survival in which tamoxifen prevents repression of antioxidant proteins, such as Prx5 leading to cell survival and resistance to tamoxifen treatment.