fig1

Figure 1. The evolution of resistance to tamoxifen after long term therapy. Phase I acquired resistance develops after a year or two of therapy of estrogen receptor (ER)-positive metastatic breast cancer. Tamoxifen stimulates cell growth, but aromatase inhibitors (AIs) and fulvestrant inhibit cell growth at this stage. Phase II acquired resistance occurs after 5 years of tamoxifen treatment. Tamoxifen continues to stimulate cell growth, but E₂ induces apoptosis. Eventually, autonomous growth occurs after indefinite tamoxifen therapy for ER-positive breast cancer, which is referred as Phase III acquired resistance. Cells are unresponsive to AIs or fulvestrant, but E₂ still induces apoptosis^[11]