Tissue-Specific Regulation of Genes by Estrogen Receptors

Abstract

Estrogens are frequently used in reproductive medicine. The Women’s Health Initiative trial found that the risks of menopausal hormone therapy (MHT) exceed the benefits. The estrogens in MHT, however, were introduced prior to our understanding of the mechanism of action of estrogens. Estrogen signaling is highly complex, involving various DNA regulatory elements to which estrogen receptors bind. Numerous transcription factors and co-regulatory proteins modify chromatin structure to further regulate gene transcription. With a greater understanding of estrogen action, the major problem with the current estrogens in MHT appears to be that they are nonselective. This produces beneficial effects in bone, brain, and adipose tissue but increases the risk of breast and endometrial cancer and thromboembolism. Resurrecting MHT for long-term therapy will require the development of more selective estrogens, such as estrogen receptor (ER)β-selective estrogens and tissue-selective ERα agonists. These compounds will offer the best prospects to expand the indications of MHT and thus prevent the chronic conditions associated with menopause.

Keywords

estrogen - estradiol - estrogen receptor - gene regulation - transcription

• References

• 1 Rossouw JE, Anderson GL, Prentice RL , et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288 (3) 321-333
• 2 Santen RJ, Allred DC, Ardoin SP , et al; Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010; 95 (7, Suppl 1) s1-s66
• 3 Anderson GL, Limacher M, Assaf AR , et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291 (14) 1701-1712
• 4 Ettinger B, Grady D, Tosteson AN, Pressman A, Macer JL. Effect of the Women’s Health Initiative on women’s decisions to discontinue postmenopausal hormone therapy. Obstet Gynecol 2003; 102 (6) 1225-1232
• 5 LaCroix AZ, Chlebowski RT, Manson JE , et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011; 305 (13) 1305-1314
• 6 Kuiper GG, Carlsson B, Grandien K , et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997; 138 (3) 863-870
• 7 Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR. Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: insights into the structural determinants favoring a differential subtype binding. Endocrinology 2006; 147 (9) 4132-4150
• 8 Heldring N, Pike A, Andersson S , et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87 (3) 905-931
• 9 Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB. Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus. J Clin Endocrinol Metab 1997; 82 (10) 3509-3512
• 10 Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS. Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology 1997; 138 (11) 4613-4621
• 11 Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol 2005; 67: 285-308
• 12 Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res 2004; 64 (1) 423-428
• 13 Ström A, Hartman J, Foster JS, Kietz S, Wimalasena J, Gustafsson JA. Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci U S A 2004; 101 (6) 1566-1571
• 14 Hartman J, Edvardsson K, Lindberg K , et al. Tumor repressive functions of estrogen receptor beta in SW480 colon cancer cells. Cancer Res 2009; 69 (15) 6100-6106
• 15 Paruthiyil S, Cvoro A, Tagliaferri M, Cohen I, Shtivelman E, Leitman DC. Estrogen receptor β causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2. Breast Cancer Res Treat 2011; 129 (3) 777-784
• 16 Minutolo F, Macchia M, Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor β ligands: recent advances and biomedical applications. Med Res Rev 2011; 31 (3) 364-442
• 17 Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 2001; 44 (24) 4230-4251
• 18 Harris HA, Albert LM, Leathurby Y , et al. Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Endocrinology 2003; 144 (10) 4241-4249
• 19 Cvoro A, Paruthiyil S, Jones JO , et al. Selective activation of estrogen receptor-beta transcriptional pathways by an herbal extract. Endocrinology 2007; 148 (2) 538-547
• 20 Mersereau JE, Levy N, Staub RE , et al. Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist. Mol Cell Endocrinol 2008; 283 (1-2) 49-57
• 21 Grady D, Sawaya GF, Johnson KC , et al. MF101, a selective estrogen receptor beta modulator for the treatment of menopausal hot flushes: a phase II clinical trial. Menopause 2009; 16 (3) 458-465
• 22 Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990; 247 (4940) 322-324
• 23 Giroux V, Bernatchez G, Carrier JC. Chemopreventive effect of ERβ-selective agonist on intestinal tumorigenesis in Apc(Min/ + ) mice. Mol Carcinog 2011; 50 (5) 359-369
• 24 Shaaban AM, O’Neill PA, Davies MP , et al. Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Am J Surg Pathol 2003; 27 (12) 1502-1512
• 25 Mostafaie N, Kállay E, Sauerzapf E , et al. Correlated downregulation of estrogen receptor beta and the circadian clock gene Per1 in human colorectal cancer. Mol Carcinog 2009; 48 (7) 642-647
• 26 Cvoro A, Yuan C, Paruthiyil S, Miller OH, Yamamoto KR, Leitman DC. Cross talk between glucocorticoid and estrogen receptors occurs at a subset of proinflammatory genes. J Immunol 2011; 186 (7) 4354-4360
• 27 Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA, Leitman DC. Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J Immunol 2008; 180 (1) 630-636
• 28 Shumaker SA, Legault C, Rapp SR , et al; WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289 (20) 2651-2662
• 29 Cauley JA, Robbins J, Chen Z , et al; Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003; 290 (13) 1729-1738
• 30 Jackson RD, Wactawski-Wende J, LaCroix AZ , et al; Women’s Health Initiative Investigators. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. J Bone Miner Res 2006; 21 (6) 817-828
• 31 Margolis KL, Bonds DE, Rodabough RJ , et al; Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia 2004; 47 (7) 1175-1187
• 32 Bonds DE, Lasser N, Qi L , et al. The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial. Diabetologia 2006; 49 (3) 459-468
• 33 Kanaya AM, Herrington D, Vittinghoff E , et al; Heart and Estrogen/progestin Replacement Study. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138 (1) 1-9
• 34 Stampfer MJ, Colditz GA, Willett WC , et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med 1991; 325 (11) 756-762
• 35 van Seumeren I. Weight gain and hormone replacement therapy: are women’s fears justified?. Maturitas 2000; 34 (Suppl 1) S3-S8
• 36 Polotsky HN, Polotsky AJ. Metabolic implications of menopause. Semin Reprod Med 2010; 28 (5) 426-434
• 37 Espeland MA, Stefanick ML, Kritz-Silverstein D , et al; Postmenopausal Estrogen-Progestin Interventions Study Investigators. Effect of postmenopausal hormone therapy on body weight and waist and hip girths. J Clin Endocrinol Metab 1997; 82 (5) 1549-1556
• 38 Jensen LB, Vestergaard P, Hermann AP , et al. Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study. J Bone Miner Res 2003; 18 (2) 333-342
• 39 Mattiasson I, Rendell M, Törnquist C, Jeppsson S, Hulthén UL. Effects of estrogen replacement therapy on abdominal fat compartments as related to glucose and lipid metabolism in early postmenopausal women. Horm Metab Res 2002; 34 (10) 583-588
• 40 Gower BA, Muñoz J, Desmond R, Hilario-Hailey T, Jiao X. Changes in intra-abdominal fat in early postmenopausal women: effects of hormone use. Obesity (Silver Spring) 2006; 14 (6) 1046-1055
• 41 Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314 (1) 1-16
• 42 Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 2004; 33 (2) 283-303
• 43 Potenza MV, Mechanick JI. The metabolic syndrome: definition, global impact, and pathophysiology. Nutr Clin Pract 2009; 24 (5) 560-577
• 44 Cho GJ, Lee JH, Park HT , et al. Postmenopausal status according to years since menopause as an independent risk factor for the metabolic syndrome. Menopause 2008; 15 (3) 524-529
• 45 Smith EP, Boyd J, Frank GR , et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994; 331 (16) 1056-1061
• 46 Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us?. Endocr Rev 1999; 20 (3) 358-417
• 47 Windahl SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C. Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice. J Clin Invest 1999; 104 (7) 895-901
• 48 Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A 2000; 97 (23) 12729-12734
• 49 Lindberg MK, Alatalo SL, Halleen JM, Mohan S, Gustafsson JA, Ohlsson C. Estrogen receptor specificity in the regulation of the skeleton in female mice. J Endocrinol 2001; 171 (2) 229-236
• 50 Bryzgalova G, Lundholm L, Portwood N , et al. Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab 2008; 295 (4) E904-E912
• 51 Lundholm L, Bryzgalova G, Gao H , et al. The estrogen receptor alpha-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms. J Endocrinol 2008; 199 (2) 275-286
• 52 Gao H, Bryzgalova G, Hedman E , et al. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol 2006; 20 (6) 1287-1299
• 53 Roesch DM. Effects of selective estrogen receptor agonists on food intake and body weight gain in rats. Physiol Behav 2006; 87 (1) 39-44
• 54 Harris HA, Katzenellenbogen JA, Katzenellenbogen BS. Characterization of the biological roles of the estrogen receptors, ERalpha and ERbeta, in estrogen target tissues in vivo through the use of an ERalpha-selective ligand. Endocrinology 2002; 143 (11) 4172-4177
• 55 Kushner PJ, Agard DA, Greene GL , et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 2000; 74 (5) 311-317
• 56 McKay LI, Cidlowski JA. Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism. Mol Endocrinol 1998; 12 (1) 45-56
• 57 Cvoro A, Tzagarakis-Foster C, Tatomer D, Paruthiyil S, Fox MS, Leitman DC. Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression. Mol Cell 2006; 21 (4) 555-564
• 58 Krishnan V, Wang X, Safe S. Estrogen receptor-Sp1 complexes mediate estrogen-induced cathepsin D gene expression in MCF-7 human breast cancer cells. J Biol Chem 1994; 269 (22) 15912-15917
• 59 Carroll JS, Liu XS, Brodsky AS , et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 2005; 122 (1) 33-43
• 60 Laganière J, Deblois G, Lefebvre C, Bataille AR, Robert F, Giguère V. From the cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc Natl Acad Sci U S A 2005; 102 (33) 11651-11656
• 61 Lonard DM, Lanz RB, O’Malley BW. Nuclear receptor coregulators and human disease. Endocr Rev 2007; 28 (5) 575-587
• 62 Kang YK, Guermah M, Yuan CX, Roeder RG. The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro. Proc Natl Acad Sci U S A 2002; 99 (5) 2642-2647
• 63 Levine M, Tjian R. Transcription regulation and animal diversity. Nature 2003; 424 (6945) 147-151
• 64 Shibata H, Spencer TE, Oñate SA , et al. Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action. Recent Prog Horm Res 1997; 52: 141-164; discussion 164–165
• 65 Billon N, Dani C.. Developmental origins of the adipocyte lineage: new insights from genetics and genomics studies. Stem Cell Rev 2011; ; March 2 (Epub ahead of print)
• 66 Vivar OI, Zhao X, Saunier EF , et al. Estrogen receptor beta binds to and regulates three distinct classes of target genes. J Biol Chem 2010; 285 (29) 22059-22066
• 67 Charn TH, Liu ET, Chang EC, Lee YK, Katzenellenbogen JA, Katzenellenbogen BS. Genome-wide dynamics of chromatin binding of estrogen receptors alpha and beta: mutual restriction and competitive site selection. Mol Endocrinol 2010; 24 (1) 47-59
• 68 Liu Y, Gao H, Marstrand TT , et al. The genome landscape of ERalpha- and ERbeta-binding DNA regions. Proc Natl Acad Sci U S A 2008; 105 (7) 2604-2609
• 69 Paruthiyil S, Cvoro A, Zhao X , et al. Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists. PLoS ONE 2009; 4 (7) e6271
• 70 Monroe DG, Secreto FJ, Subramaniam M, Getz BJ, Khosla S, Spelsberg TC. Estrogen receptor alpha and beta heterodimers exert unique effects on estrogen- and tamoxifen-dependent gene expression in human U2OS osteosarcoma cells. Mol Endocrinol 2005; 19 (6) 1555-1568
• 71 Krum SA, Miranda-Carboni GA, Lupien M, Eeckhoute J, Carroll JS, Brown M. Unique ERalpha cistromes control cell type-specific gene regulation. Mol Endocrinol 2008; 22 (11) 2393-2406
• 72 Lupien M, Brown M. Cistromics of hormone-dependent cancer. Endocr Relat Cancer 2009; 16 (2) 381-389
• 73 Carroll JS, Meyer CA, Song J , et al. Genome-wide analysis of estrogen receptor binding sites. Nat Genet 2006; 38 (11) 1289-1297
• 74 Lupien M, Eeckhoute J, Meyer CA , et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 2008; 132 (6) 958-970
• 75 Welboren WJ, van Driel MA, Janssen-Megens EM , et al. ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands. EMBO J 2009; 28 (10) 1418-1428
• 76 Lin CY, Vega VB, Thomsen JS , et al. Whole-genome cartography of estrogen receptor alpha binding sites. PLoS Genet 2007; 3 (6) e87
• 77 Levy N, Zhao X, Tang H, Jaffe RB, Speed TP, Leitman DC. Multiple transcription factor elements collaborate with estrogen receptor alpha to activate an inducible estrogen response element in the NKG2E gene. Endocrinology 2007; 148 (7) 3449-3458
• 78 Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004; 25 (1) 45-71
• 79 Bulynko YA, O’Malley BW. Nuclear receptor coactivators: structural and functional biochemistry. Biochemistry 2010; ; December 29 (Epub ahead of print)
• 80 Misiti S, Schomburg L, Yen PM, Chin WW. Expression and hormonal regulation of coactivator and corepressor genes. Endocrinology 1998; 139 (5) 2493-2500
• 81 Molenda HA, Kilts CP, Allen RL, Tetel MJ. Nuclear receptor coactivator function in reproductive physiology and behavior. Biol Reprod 2003; 69 (5) 1449-1457
• 82 Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002; 295 (5564) 2465-2468
• 83 Karmakar S, Foster EA, Smith CL. Unique roles of p160 coactivators for regulation of breast cancer cell proliferation and estrogen receptor-alpha transcriptional activity. Endocrinology 2009; 150 (4) 1588-1596
• 84 Al-Dhaheri M, Wu J, Skliris GP , et al. CARM1 is an important determinant of ERα-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res 2011; 71 (6) 2118-2128
• 85 Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28 (10) 1057-1068