Sitive breast cancer cell lines; though in tamoxifen resistant cell lines, the ER coactivator AIB-1/SRC-3 competes with PAX2 for binding, major to improved HER2 transcription[38]. Moreover, HER2 activation decreases ER level and increase ER phosphorylation, even inside the absence of estrogen[38-40]. HER2 signaling alters ER mediated transcription via disrupting the interac-DEREGULATION OF CLASSIC ESTROGEN SIGNALINGThe classic function of ER is its nuclear function, also referred to as genomic activity, to regulate the expression of genes vital for standard and cancer cell proliferation and survival[3]. The nuclear estrogen receptors (ER and ERb) have comparable structure, consisting of a central DNA-binding domain flanked by two autonomous transcriptional activation domains. In classic estrogen signaling, ligand-bound ER activates gene expression-either through direct binding of dimeric ER to distinct DNA response elements in complexes such as co-activators, or function as a coregulator by way of protein-protein interactions with other transcription components, such as activation protein 1 (Ap1), specificity protein 1 (Sp1) and nuclear factor (NF-kB) to facilitate binding to serum response elements and activation of transcription[28-30]. Mechanisms of endocrine resistance include the loss of ER expression which happens in 15 -20 of resistant breast cancers, ER mutations which present in 1 of ER-positive tumors, the expression of ER splicing variants, especially the truncated variant ER36, and estrogen associated receptors (ERR)[11,14,31-33]. Deregulation of ER co-regulators has been implicated in endocrine resistance at the same time. One example is, improved Ap1 and NF-kB transcriptional activity are associated with endocrine resistance. Overexpression of nuclearWJCO|www.wjgnetAugust ten, 2014|Volume 5|Challenge three|Zhao M et al .EGA manufacturer Advances in endocrine-resistant breast cancerE RTKs: HER2 EGFR IGFR FGFR Breast cancer microenviroment Extracellular Space integrins PI3 CoA ER PTE AKT mTO A TFs RAS RAF MEK p38 Src FAK JNK CytoplasmGFstressER B TFsMAPK CCoA ER ERCoA ER APCoA TF TF Gene expressionNucleusFigure 1 Estrogen receptor action at molecular level.5-Ethynyl-2′-deoxyuridine Epigenetic Reader Domain A: Ligand dependent activation: in classic estrogen signaling, ligand-bound ER activates gene expressioneither through direct binding of dimeric ER to distinct DNA response components in complexes like co-activators, or function as a coregulator through protein – protein interactions with other transcription components to facilitate binding to serum response elements and activation of transcription; B: Ligand independent activation: the ER may also be activated by ligand independent style, as a consequence of signaling events downstream of membrane receptor tyrosine kinases (RTKs); C: Nongenomic mechanisms: signaling could be mediated through non-genomic mechanisms by ER which is localized at the cell membrane or inside the cytoplasm.PMID:23916866 ER: Estrogen receptor; mTOR: Mammalian target of rapamycin; FGFR: Fibroblast growth factor receptor; IGF-1R: Insulin-like development factor-1 receptor; EGFR: Epidermal growth aspect receptor.tion between ER and its coregulators (corepressors and coactivators). HER2 also activates downstream signaling pathways, for example the phosphoinositide 3-kinase (PI3K)/ AKT pathway and mitogen activated kinase (MAPK) pathway, as discussed later[3,15,19]. The interdependence of ER and HER2 pathways is highlighted by examples in which therapy with AIs or downregulation of ER with fulvestrant has inhibite.
