Mechanisms of endocrine resistance in breast cancer cells. (A) Mechanisms of tamoxifen (TAM) resistance may involve the loss of estrogen receptor (ER) alpha expression, which can be achieved by methylation of CpG islands or histone deacetylase activity in the ESR1 promoter. Tamoxifen-resistant growth is also stimulated by the upregulation of growth factor signaling pathways (HER2, IGFR1, and FGFR1) and subsequent activation of the mitogen-activated protein kinase (MAPK) cascade or phosphoinositide 3-kinase (PI3K) pathway. Finally, tamoxifen has even been shown to stimulate the growth of breast cancer cells when bound to certain coactivators, such as AIB1, and this is especially true in HER2-expressing cells. (B) The mechanisms of aromatase inhibitor (AI) resistance share similarities with tamoxifen resistance, especially in terms of growth factor pathway upregulation. The enhanced activity of growth factors such as MAPK can result in estrogen-independent phosphorylation and activation of ERα. In addition to growth factor signaling, interferon response genes and anti-apoptotic proteins have also been shown to have increased expression in AI-resistant cells. AIB1, amplified in breast cancer 1; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1.