cell signalling pathway activated by oestrogen
10,11 On the other hand, ERβ signaling can induce G2 cell cycle arrest and inhibit the estrogen-induced cancer cell proliferation. The membrane receptor may also form homodimers or couple with other proteins, such as caveolins, flotillins (12, 35), and coactivator protein modulator of nongenomic actions of the estrogen receptor (MNAR)/proline-, glutamic acid-, and leucine-rich protein-1 (PELP1; ref. TGF-β signaling pathway is closely associated with p21, p27, c-myc and c-fos in cancer . Estrogen receptors have both transcriptional and non-genomic functions and response to both estrogen and other signals that arise from growth factor signaling pathways. Nature and activity of extranuclear ERs.ERα gene codes for a major 66-kDa transcript and a minor 46-kDa isoform lacking portions of the NH2-terminal region of full-length ERα (26, 27). ER+ and/or PR+, HER2-overexpressing tumors respond poorly to endocrine therapy (57–61), and a meta-analysis of seven clinical studies indicates that metastatic breast cancers with HER2 overexpression are tamoxifen resistant (62). Some type I nuclear receptors are activated, in part, upon binding their respective ligand in the cytoplasmic compartment. Using ERα+ MCF-7 cells engineered for constitutive activation and/or overexpression of different components of growth factor signaling pathways, we have developed models to mimic the MAPK hyperactivation seen in ERα− breast cancer (19, 21 – 23). All Rights Reserved. ERα associated with membrane is detected by the use of controlled homogenization procedures with quantitative subcellular fractionation to limit extraction artifacts (11, 29) and by antibodies directed to different domains of nuclear ERα in intact breast (30–32), NSCLC (13, 14), and pituitary tumor cells (33), as well as in nonmalignant vascular cells (34). However, resistance to endocrine therapy usually emerges, leading to tumor progression and poor patient survival. Previously, estrogen‐responsive MCF7 cells have been transduced with BCAR3, EGFR and BCAR4, and each gene induced antiestrogen resistance. The 46-kDa ER also occurs in membranes of endothelial (27) and breast (35) cells where it may form part of a signaling complex. Copyright © 2021 by the American Association for Cancer Research. Structure and activity of nuclear ER. Estrogen response element–dependent and alternate transcription sites may be activated. Currently, combination therapies directed to extranuclear and nuclear ER as well as to growth factor signaling pathways are being assessed in the clinic, and hopefully, these new strategies will offer improved antitumor efficacy for patients afflicted with hormone receptor–positive tumors. J Biol Chem. However, about one third of estrogen-induced genes lack functional estrogen response elements, and estrogens indirectly regulate transcription of these genes by modulating activity of other transcription factors such as activator protein-1, Elk-1, serum response factor, cyclic AMP–responsive element binding protein, nuclear factor κB, and signal transducers and activators of transcription (4). Cell 157(1), 255–66. However, ER also regulates the expression of many genes without direct binding to DNA. Generally, a signaling pathway is the phosphorylation of a few specific target-cell proteins, which changes their activities and thus the activities of the cell. Receptors help in recognising the signal molecule (legand). Type II nonsteroid nuclear receptors include the thyroid hormone receptors (TRα and β), retinoic acid receptors (RARα, β, and γ), vitamin D receptor (VDR), and peroxisome proliferator-activated receptors (PPARα, β, and γ). Ser118 may be the substrate of the transcription regulatory kinase CDK7, whereas Ser167 may be phosphorylated by p90RSK and Akt. Membrane-Associated Estrogen Receptor Signaling Pathways in Human Cancers, Therapeutic Targeting of the Liver Microenvironment, Targeting the Protein Kinase Wee1 in Cancer, Metabolic Control of Histone Methylation and Gene Expression, Cancer Epidemiology, Biomarkers & Prevention, estrogen receptor, HER2 receptor, EGFR, lipid rafts, steroid receptor coactivator. This approach is based on blocking the activity of estrogens and their receptors, ERα and ERβ (2). However, localization and activity of ER at plasma membrane is stimulated by posttranslational palmitoylation of Cys447 in the ligand-binding domain of ERα (14, 27, 40). ERα has six major functional domains including an NH2-terminal transactivation domain, an adjacent DNA-binding domain, and a portion involved in hormone-binding, receptor dimerization, and activity of a second transactivation region (16–18). ESTROGENS ARE STEROID hormones that regulate growth, differentiation, and function in a broad range of target tissues in the human body. Orphan nuclear receptors are nuclear receptors where the endogenous ligands have not been identified. The nuclear receptor superfamily are ligand-activated transcription factors that play diverse roles in cell differentiation/development, proliferation, and metabolism and are associated with numerous pathologies such as cancer, cardiovascular disease, inflammation, and reproductive abnormalities. Moreover, the observation that long-term estrogen-deprived MCF7 cells (with increased estrogen sensitivity) exhibit up-regulation of ErbB2 and Erk1/2 , and increased Akt phosphorylation and mammalian target of rapamycin (mTOR) effector activation also indicates that up-regulation of growth factor signaling is fundamental to the adaptation of breast cancer cells to low estrogen levels in … Further, membrane ERs do not occur in ER-negative MCF-7 breast tumor subclones that lack nuclear ER, and these cells, unlike ER-positive MCF-7 cells, do not show rapid estrogen-induced phosphorylation of steroid receptor coactivator AIB1 (35). Estrogen is a steroid hormone that is responsible for the regulation of growth, differentiation and function of the reproductive system and several other target tissues. This allows direct binding of the ligand-ER complex with steroid receptor coactivators and estrogen response elements (ERE) in DNA, leading to changes in gene transcription that regulate growth, differentiation, apoptosis, and angiogenesis. The 447-cysteine site of ERα is capable of palletization and this effect is related to caveolin. Although most ERs localize in tumor cell nuclei, a significant pool of ERs occurs in extranuclear sites in cell lines and archival breast cancer and NSCLC cells (14, 28). Acute signaling by estrogen in target cells, such as breast tumors and non–small cell lung cancer (NSCLC), is now widely reported and involves nuclear and extranuclear ERs acting in concert with growth factor receptor pathways to promote downstream signaling for cell proliferation and survival (see refs. Laboratory models show that long-term estrogen deprivation that mimics low estrogen levels produced by aromatase inhibition eventually elicits adaptive changes in tumor cell behavior, with emergence of hypersensitivity to estrogen and increased aromatase activity (70, 71). Tumor cells may also circumvent pharmacologic blockade of estrogen response pathways by enhanced expression of aromatase to increase estrogen biosynthesis. 11, 12, 49). Trastuzumab prolongs progression-free survival in hormone-dependent and HER2-positive metastatic breast cancer. Legend. The classic mechanism of hormone action involves estrogen binding to ER in the nucleus, thus promoting association with specific estrogen response elements in the promoters of target genes (3). We would like to thank Prof. David J. Mangelsdorf, University of Texas Southwestern Medical Center for reviewing this diagram. Sign In to Email Alerts with your Email Address. 47, 52, 75, 81, 82). sites in target genes. The TGF-β/Smad signaling pathway, which is activated in prostate cancer, has a regulatory effect on the cell cycle. T… In this setting, HER2 overexpression triggers signaling for increased ER phosphorylation (19, 48, 63) and loss of the inhibitory effect of tamoxifen on ER-mediated transcription (49, 61, 64–66). How ER associates with membranes is another challenging question. Recent clinical data on breast tumors also suggest that the ER+/PR− phenotype, in particular, associates with high expression of extranuclear ER and enhanced AKT signaling (28) and may identify tumors driven primarily by growth factor receptor signaling (47, 49, 67). Transmembrane growth factor receptors may also provide docking sites (32, 42). In breast cancer, IL6/STAT3 signaling has previously been linked to estrogen receptor α (ER) function. Second, estrogen activates human colon carcinoma-derived Caco-2 cell growth through a rapid and reversible stimulation of intermediates in the signal transduction pathway of the c-Src-related tyrosine kinases c-Src and c-Yes, as well as of ERK1 and ERK2 .