Fig. 3

mechanism of resistance to endocrine therapy with tamoxifen (TAM) in breast cancer. Increasing the expression and activity of tyrosine kinase receptor family proteins, such as HER2, EGFR, IGFR, and GPR30, gives rise to alterations in translation signals and, thus, acquired resistance to TAM. These events lead to aberrant activation of cAMP/PKA, MAPK/ERK, and PI3K/AKT signaling pathways. Activation of these kinase pathways results in phosphorylation of ER and its co-activators such as A1B1, MED1, or CARM1, thereby activating proliferation and inhibiting apoptosis. Also, in the condition of deregulating ER, HER2-mediated signaling can be increased, and transcription factors such as Sp1, AP-1, and NF-κB can be activated, hence promoting oncogene transcription. Likewise, factors such as FOXA1 and PBX1 can recruit ER to specific genomic sites. In addition, mutations in the tumor suppressor protein have been seen to escalate phosphorylation of PI3K/AKT in ER⁺ tumors, resulting in therapeutic resistance. Incidentally, KDM6B and EZH2, which modify histones and cause aberrant protein phosphorylation, can lead to resistance to endocrine therapy from the reactivation of genes