Estrogen (ER) receptor biology: Implications for HRT? Dr. Christoph A. Meier Endocrine Unit University Hospital Geneva

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1 Estrogen (ER) receptor biology: Implications for HRT? Dr. Christoph A. Meier Endocrine Unit University Hospital Geneva

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3 Estrogens prevent postmenopausal bone-loss

4 HRT & osteoporosis bip & estrogen bip estrogen placebo

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9 Can estrogen actions be tissue-and gene- specific? How do estrogens act?

10 Molecular targets for pharmacotherapy membrane receptors 50% enzymes 20% hormones, growth actors 15% ion channels 5% nuclear receptors 2% other 5% n=500

11 Membrane receptors as pharmaclogical targets β-blockers ARB somatostatin antagonists peptides, proteins, catech. insulin, oxytocin, LH-RH, LH, FSH, PRL adrenaline et analogues, G-CSF, EPO, TPO P Ca ++ enzymes transcription factors mrna, protein synthesis cellular effects

12 Nuclear receptors L L L steroids (gluco-, mineralocort, E2, progest., androgens) 1,25-(OH) 2 -vitamine D T3 retinoic acid metabolites (FFA, PG,..) orphan receptors cellular effects mrna, protein synthesis

13 ER binding sites QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

14 Nuclear receptors as pharmacological targets AGONISTS T3, prednisone, E 2, L progesterone, testosterone, vitamine D isotretinoine (Roaccutan ) all-trans RA (ATRAC) raloxifene, tamoxifene glitazones Ant L L mrna, protein synthesis PUFA Ant cellular effects ANTAGONISTS flutamide, cyproterone acetate RU486 tamoxifene, raloxifene

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16 Hereditary mutations in nuclear receptors NH 2 DNA binding ligand binding COOH ERα AR GR TR VDR [Gln] n E 2 resistance (recessive) T resistance (X chr.) (Reifenstein, testicular feminisation, Kennedy syndrome) GC resistance (recessive) TH resistance (dominant) VDDR II (recessive)

17 Testicular feminization XY

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19 Rec Prog Horm Res 57: 181

20 Spino-bulbar Muscular Atrophy NH 2 CAG >40 DNAbinding Hinge Ligand binding /dimerization/ transactivation COOH Expansion of a Gln-repeat in the N-terminal trans-activation domain Clinical presentation: - delayed onset (30-50 y) of progressive atrophy of spinal and bulbar muscles (cramps, tremor, weakness of the tongue, facial muscles and prox. limb girdle muscles) - mild, late-onset androgen resistance Pathogenesis: 1. dysfunctional AR 2. accumulation of a toxic protein? (in males only)

21 Estrogen resistance NH 2 transactivation C NEJM, 331: 1056f (1994)

22 ER polymorphisms in humans

23 NEJM 346: 967f (2002)

24 Somatic mutations in nuclear receptors ER GR AR breast cancer: dominant negative & positive mutations paradoxical activation by tamoxifene glucocorticoid resistance? (lymphomas, myelomas) prostate cancer RAR PML

25 Activation of ER E2 ER ER E2 E2 ER E2 ER GTF, RNApII

26 Transcriptional regulation differentiation differentiation mrna protéines

27 E2 Activation of nuclear receptors Co-repressor ER ER E2 E2 ER E2 ER Coactivator GTF, RNApII

28 Chromatin Nature 389: 251f 1997

29 Chromatin structure Co-repressor RXR RAR histone deacetylase DNA ATRA histone octamer acetyl group RXR Coactivator = histone acetylase ATRA RAR RNA polymerase II DNA

30 Chromatin opening

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32 God does not play dice, he prefers Lego Pierre Chardin, 1997

33 Knock-out of the co-activator SRC-1 uterus (stimulated) breast tissue (8 weeks) SRC-1 Science 279:1922f (1998)

34 Overexpression of the co-activator AIB-1 in breast cancer normal mammary cells breast cancer cells Science 277: 965f (1997)

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36 Tamoxifene BMD But: endometrial hyperplasia, hot flashes J.Clin.Oncol. 14:76f (1996)

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38 SERMs E2 AGONIST all tissues ANTAGONIST tamoxifene endometrium, breast bone, lipids raloxifène bone, lipids breast, endometrium ICI 164,384 all tissues

39 How do SERMs work Co-repressor ER ER +++ bone, liver R ER R R ER Ralox-coactivator GTF, RNApII endometrium, breast R --- R +++ R ER transcription factors GTF, RNApII E2-coactivaour ER ER

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41 Raloxifene E2 raloxifene Nature 389: 753f (1997)

42 Effects of raloxifene on bone placebo placebo

43 Effects of raloxifene on lipids

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48 Another type of SERMs: Endocrine disrupters

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52 1995 Cloning of a second ER...

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54 Role of the different ER subtypes?

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56 E2 E2 E2 & ralox E2 & ralox ralox ralox

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66 Molecular targets for pharmacotherapy membrane receptors 50% enzymes 20% hormones, growth actors 15% ion channels 5% nuclear receptors 2% other 5% n=500

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69 'This is not a pipe' R. Magritte, La trahison des images 1929

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