- Open Access
Estrogen receptor transcription and transactivation Basic aspects of estrogen action
© Current Science Ltd 2000
- Received: 29 February 2000
- Accepted: 19 June 2000
- Published: 1 October 2000
Estrogen signaling has turned out to be much more complex and exciting than previously thought; the paradigm shift in our understanding of estrogen action came in 1996, when the presence of a new estrogen receptor (ER), ERβ, was reported. An intricate interplay between the classical ERα and the novel ERβ is of paramount importance for the final biological effect of estrogen in different target cells.
- central nervous system
- estrogen receptor β
- estrogen receptor knockout mice
Jensen and Jacobsen were the first to describe that the biological effects of estrogen are mediated by a receptor protein . The cloning of the ER, today renamed ERα, was reported in 1986 [2,3]. For a long time, it was believed that only one ER existed; however, in 1995 a second ER, ERβ, was cloned from a rat prostate cDNA library by Gustafsson and colleagues [4**]. This finding has lead to a paradigm shift in our understanding of estrogen action, as will be evident from the different reviews in this issue of Breast Cancer Research.
Since the discovery of ERβ in rat prostate, several groups have reported the cloning of ERβ from other species [5,6,7] or different sized ERβ isoforms, some with extended N-termini and others with truncations and/or insertions in the C-terminal ligand binding domain (LBD). The original ERβ clone encodes a protein of 485 amino acids, designated ERβ-485. ERβ-503 has an 18 amino acid residue in frame insertion into the LBD, and has a considerably lower affinity for E2 than ERβ-485. Both ERβ-503 and ERβ-485 bind to a consensus estrogen response element (ERE) and heterodimerize with each other and with ERβ [8,9]. The coactivator SRC-1 interacts with both ERα and ERβ-485 in an estrogen-dependent manner but not with ERβ-503 . An additional ERβ isoform, ERβcx , is identical to ERβ-530 except that the last 61 C-terminal amino acids (exon 8) are replaced by 26 unique amino acid residues. The ERβcx isoform shows no ligand binding activity and has no capacity to activate transcription of an estrogen-sensitive reporter gene . Furthermore, ERβcx shows preferential heterodimerization with ERα rather than with ERβ, inhibiting ERα DNA binding and having a dominant negative effect on ligand-dependent ERβ reporter gene transactivation .
Various alternatively spliced forms of ERα have also been reported [11,12,13,14,15,16]. Whether all isoforms or differentially spliced versions of ERα and ERβ, respectively, are expressed as proteins or have any major biological role warrants further investigation.
ERα and ERβ are similar in their architecture to the other members of the steroid/thyroid hormone nuclear receptor superfamily [17,18,19,20,21,22] in that they are composed of independent but interacting functional domains. Ligand-induced gene modulation by hormone receptors is due to ligand-induced conformational changes in the receptor. These conformational changes lead to receptor dimerization, receptor-DNA interaction, recruitment of and interaction with co-activators and other transcription factors, and the formation of a preinitiation complex [23,24,25,26].
In ERα, the N-terminal A/B domain encodes activation function 1 (AF1) [27,28,29,30]. Synthetic antiestrogens such as tamoxifen, raloxifene and ICI 164,384 induce a partial agonism on an ERE-based reporter gene in the presence of ERα but pure estrogen antagonism with ERβ [7,31*,32]. In ERα, different parts of AF1 are required to mediate the agonism of E2 and the partial agonism of tamoxifen , a particular function of ERα AF1 that is missing in ERβ . Differences in the amino-terminal regions of ERα and ERβ thus constitute a possible explanation for the difference between ERα and ERβ in their response to various estrogens including antagonists such as tamoxifen and raloxifene.
The C or DNA binding domains of ERα and ERβ are highly homologous  with identical P-box sequences and, therefore, ERα and ERβ are likely to bind to different EREs with similar specificity and affinity.
Activation function 2 (AF2) in the LBD constitutes the ligand-dependent transcription activation function of nuclear receptors [26,33,34,35,36,37]. In the crystal structure of ERα LBD, complexed with E2 [38**], the agonist-induced positioning of H12 over the ligand-binding pocket has been shown to form the basis for the AF2 coactivator recruitment and interaction surface, together with amino acid residues in H3, H4, and H5. In contrast, in the ERα and ERβ LBD-raloxifene complexes, respectively [38**,39], H12 was displaced from its agonist position over the ligand-binding cavity and instead occupied the hydrophobic groove formed by H3, H4, and H5, foiling the coactivator interaction surface. Although E2 and raloxifene bind to the same cavity in the receptor, these ligands induce a different conformation of H12 in the LBD, discriminating an agonistic effect by E2 from estrogen antagonism by raloxifene. Surprisingly, H12 in the ERβ genistein structure did not adopt an agonist conformation  but a position more similar to an antagonist conformation, a finding in agreement with the partial (60-70% of E2) agonism of genistein acting via ERβ on an ERE-driven reporter gene in cells [31*]. It is evident that different ligands induce different receptor conformations [24,40], and that different conformations of the receptor affect the agonist efficacy and potency of ligands.
An interesting difference between ERα and ERβ is also seen on an AP1 site. In the presence of ERα, typical agonists such as E2 and diethylstilbestrol as well as the anti-estrogen tamoxifen function as equally efficacious agonists in the AP1 pathway, raloxifene being only a partial activator. In contrast, in the presence of ERβ, the antiestrogens tamoxifen and raloxifene behave as fully competent agonists in the AP1 pathway, while estradiol acts as an antagonist inhibiting the activity of both tamoxifen and raloxifene [41**].
ERβ is widely distributed in the organism. ERβ was originally cloned from rat prostate, which is one of the most ERβ dense in the body. The ovaries in the female rodent show a corresponding abundance of ERβ, mainly in the granulosa cells. The tissues that appear to be richest in ERβ are the central nervous system, the cardiovascular system, the lung, the kidney, the urogenital tract, the mammary gland, the colon, the immune system and the reproductive organs. The significance of ERβ and ERα in some tissues will now be discussed.
The importance of estrogens in the development of female breast tissue is well documented. Female aromatase deficient patients, unable to convert C19 steroids (eg testosterone) to estrogens, showed no sign of breast development at the onset of puberty [42,43,44]. Administration of estrogen to the two described female patients, however, led to normal prepubertal and postpubertal breast development. ERα knockout female mice have lost their capacity to develop mammary gland tissue beyond the embryonic and fetal stages despite elevated levels of circulating estrogens (17β-estradiol).
More than 70% of primary breast cancers in women are 'ER' (actually ERα) positive and show estrogen-dependent growth , and undergo regression when deprived of supporting hormones. Patients whose breast tumors lack significant amounts of ER rarely respond to endocrine ablation or treatment with antiestrogens, whereas most patients with ER-containing cancers benefit from such treatment [46,47]. Immunochemical determination of ER in tumor biopsies has become a routine clinical procedure on which the choice of therapy is based. However, the currently available immunochemical procedures for ER measurements are based on ERα-specific antibodies that do not detect ERβ protein (unpublished observations).
ERβ mRNA and protein have been detected in human breast cancer biopsies and in human breast cancer cell lines [6,48,49,50]. With the use of receptor specific antibodies, both ERα and ERβ were expressed in the normal rat mammary gland, but the presence and cellular distribution of the two receptors was distinct [51*]. Furthermore, while the level and number of cells expressing ERβ were more or less constant during prepubertal and pubertal stages, and throughout pregnancy, lactation and postlactation, the level and percentage of ERα-containing cells varied dramatically. The possible role of ERβ in normal breast tissue development and physiology or in breast cancer development and/or therapy is, however, as yet unknown [52,53*].
Estrogens are claimed to be effective in the treatment of urge incontinence in postmenopausal women (see [54,55] and references cited therein). It has recently been shown that ERβ is highly expressed in the inner epithelial cell layer of the rat bladder and urethra [56,57], which may explain the beneficial effect of estrogens in urinary incontinence and suggest that patients with urinary incontinence might benefit from ERβ-selective agonist therapy.
Estrogens have been linked with prostate pathologies. It has been shown in different species that estrogens synergize with androgens in inducing glandular hyperplasia and dysplasia, and adenocarcinoma in the prostate [58*]. Immunohistochemical studies have revealed that ERβ is the predominant ER in the prostate, located in the epithelial cells along the ductal network of the prostate. ERα has been detected only in the stromal compartment of the prostate [57,58*] (Weihua et al, manuscript submitted). ERβ-/- mice display signs of prostatic hyperplasia with aging . This suggests that ERβ may protect against abnormal prostate growth and that ERβ-selective ligands would be of clinical relevance in the prevention and treatment of neoplasia of the prostate.
Bone: development and homeostasis
There is compelling evidence that estrogens protect post-menopausal women from bone loss and the development of osteoporosis, maintaining a balance between bone resorption and bone formation [54,55,60,61,62,63]. As in other tissues, estrogens probably have both direct and indirect effects in maintaining a balanced bone metabolism. The likelihood of important direct effects of estrogens on bone is based on the presence of ERα in the bone-forming osteoblasts [64,65,66] and in the bone-resorbing osteoclasts . ERβ mRNA has been found in primary rat osteoblasts and in rat osteosarcoma cells . It has been described in immortalized human fetal osteoblasts that ERα and ERβ are differentially expressed during osteoblast differentiation in vitro .
The cardiovascular system
The risk of women developing cardiovascular disease increases dramatically after the menopause, suspected to be a consequence of the cessation of estrogen production by the ovaries. Estrogen replacement therapy has a cardiovascular protective effect in postmenopausal women, significantly decreasing the risk of developing atherosclerosis and cardiovascular disease [54,55,70,71,72,73,74].
The estrogen receptors ERα and ERβ are expressed in vascular endothelial cells [74,75,76], smooth muscle cells [77,78,79], and in myocardial cells [56,80]. Various direct effects of estrogen on vascular tissue have been reported [73,74,80,81,82]: nongenomic vasodilatation as an effect of estrogen on ion channel function  and nitric oxide synthesis [84,85,86,87]; long-term effects by modulation of, for example, prostaglandin synthase, nitric oxide synthase and endothelin gene expression [88,89,90,91,92,93]; regulation of AT1 receptor density on vascular smooth muscle cells ; and inhibition of injury-induced vascular intimal thickening [95,96,97]. Furthermore, reduced heart contractility in ovariectomized female rats was normalized following estrogen replacement , an effect explained in part by estrogen mediated changes in expression of contractile proteins [80,99]. The precise functions of ERα and ERβ in protection of the vessel wall from injury-induced hyperproliferation are still under active investigation. Estrogen can inhibit hyperproliferation of the vascular smooth muscle cells after injury in both ERα knockout and BERKO (ERβ-/-) mice [100*,101*,102*], possibly indicating that the effects of estrogen on the smooth muscle cells are not receptor mediated, but possibly also indicating that the vesssel wall is one location where ERα and ERβ have overlapping functions. The answer to the question will be found when ERα/ERβ double knockout mice are examined.
Central nervous system and the hypothalamus-pituitary axis
Estrogens are reported to influence a variety of functions in the central nervous system such as learning, memory, awareness, fine motor skills, temperature regulation, mood, and reproductive functions . Estrogens are also linked to symptoms of depression and treatment of depressive illness.
The expression patterns of ERα and ERβ, respectively, based on mRNA, autoradiographic or immunohistochemical studies of rat and mouse brain, indicate that there is selective expression of one of the two ER subtypes in certain areas of the brain, but that there are also areas where they seem to be colocalized. ERα is more abundant in the hypothalamus (preoptic, arcuate, periventricular, and ventromedial nucleus) and in selected nuclei in the amygdala (hippocampal area, medial and cortical nucleus) [104,105,106,107]. A high level of ERβ mRNA has been found in the medial preoptic, paraventricular and supraoptic nucleus of the rat hypothalamus and in the medial amygdala nucleus. Moderate to high ERβ mRNA is expressed in olfactory bulbs, the bed nucleus of the stria terminalis, the hippocampus, the cerebral cortex, the cerebellum, the midbrain raphe and the basal forebrain [103,105,106,107,108,109,110,111].
The hypothalamus-pituitary axis regulates overall endocrine homeostasis in the body. Estrogen, through effects on the hypothalamus-pituitary axis, modulates the expression and secretion of hormones such as luteinizing hormone, follicle stimulating hormone, growth hormone, and prolactin, from the anterior pituitary gland . Both ERα and ERβ are expressed in the pituitary gland but ERα predominates [112,113], particularly in the gonadotrophs and lactotrophs. Both ER subtypes are also expressed in the preoptic area of the hypothalamus, which is involved in regulating the expression of pituitary hormones, but ERβ is predominant .
Our understanding of estrogen action has undergone a radical change following the discovery of ERβ. Although not addressed in this particular review, evidence is accumulating that ERα and ERβ may indeed regulate, at least partially, separate and distinct gene networks. We are thus now beginning to have tools to grasp many of the seemingly confusing and contradictory aspects of estrogen action, particularly regarding tissue specific and cell specific effects of estrogen. Varying ratios between ERα and ERβ in different contexts seem to quite probably be of paramount importance for the finally obtained hormonal effects. This paradigm shift in our concepts of estrogen action, needless to say, will lead to many exciting new opportunities for pharmaceutical development in the field of women's health.
- Jensen EV, Jacobsen HI: Basic guides to the mechanism of estrogen action. Recent Prog Horm Res. 1962, 18: 387-414.Google Scholar
- Green S, Walter P, Kumar V, et al: Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986, 320: 134-139.PubMedView ArticleGoogle Scholar
- Greene GL, Gilna P, Waterfield M, et al: Sequence and expression of human estrogen receptor complementary DNA. Science . 1986, 231: 1150-1154.PubMedView ArticleGoogle Scholar
- Kuiper GGJM, Enmark E, Pelto-Huikko M, et al: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA. 1996, 93: 5925-5930. 10.1073/pnas.93.12.5925. This paper initiated a paradigm shift in the understanding of estrogen action, and was the first report on the second estrogen receptor ERβ.PubMedPubMed CentralView ArticleGoogle Scholar
- Mosselman S, Polman J, Dijkema R: ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996, 392: 49-53. 10.1016/0014-5793(96)00782-X.PubMedView ArticleGoogle Scholar
- Enmark E, Pelto-Huikko M, Grandien K, et al: Human estrogen receptor β - gene structure, chromosomal localisation and expression pattern. J Clin Endocrinol Met. 1997, 82: 4258-4265. 10.1210/jc.82.12.4258.Google Scholar
- Tremblay GB, Tremblay A, Copeland NG, et al: Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor β. Mol Endocrinol. 1997, 11: 352-365. 10.1210/me.11.3.353.Google Scholar
- Petersen DN, Tkalcevic GT, Koza-Taylor PH, et al: Identification of estrogen receptor β2, a functional variant of estrogen receptor β expressed in normal rat tissues. Endocrinology. 1998, 139: 1082-1092. 10.1210/en.139.3.1082.PubMedGoogle Scholar
- Hanstein B, Liu H, Yancisin M, Brown M: Functional analysis of a novel estrogen receptor-β isoform. Mol Endocrinol. 1999, 13: 129-137. 10.1210/me.13.1.129.PubMedGoogle Scholar
- Ogawa S, Inoue S, Watanabe T, et al: Molecular cloning and characterization of human estrogen receptor βcx: a potential inhibitor of estrogen action in human. Nucleic Acids Res . 1998, 26: 3505-3512. 10.1093/nar/26.15.3505.PubMedPubMed CentralView ArticleGoogle Scholar
- Fuqua SAW, Chamness GC, McGuire WL: Estrogen receptor mutations in breast cancer. J Cell Biochem. 1993, 51: 135-139.PubMedView ArticleGoogle Scholar
- Friend KE, Ang LW, Shupnik MA: Estrogen regulates the expression of several different estrogen receptor mRNA isoforms in rat pituitary. Proc Natl Acad Sci USA. 1995, 92: 4367-4371.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhang QX, Hilsenbeck SG, Fuqua SA, et al: Multiple splicing variants of the estrogen receptor are present in individual human breast tumors. J Steroid Biochem Mol Biol. 1996, 59: 251-260. 10.1016/S0960-0760(96)00120-3.PubMedView ArticleGoogle Scholar
- Friend KE, Resnick EM, Ang LW, et al: Specific modulation of estrogen receptor mRNA isoforms in rat pituitary throughout the estrous cycle and in response to steroid hormones. Mol Cell Endocrinol. 1997, 131: 147-155. 10.1016/S0303-7207(97)00098-1.PubMedView ArticleGoogle Scholar
- Murphy LC, Dotzlaw H, Leygue E, et al: Estrogen receptor variants and mutations. J Steroid Biochem Mol Biol. 1997, 62: 363-372. 10.1016/S0960-0760(97)00084-8.PubMedView ArticleGoogle Scholar
- Taylor JA, Lewis KJ, Lubahn DB: Estrogen receptor mutations. Mol Cell Endocrinol. 1998, 145: 61-66. 10.1016/S0303-7207(98)00170-1.PubMedView ArticleGoogle Scholar
- Evans RM: The steroid and thyroid hormone superfamily. Science. 1988, 240: 889-895.PubMedView ArticleGoogle Scholar
- Tsai MJ, O'Malley BW: Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994, 63: 451-486. 10.1146/annurev.bi.63.070194.002315.PubMedView ArticleGoogle Scholar
- Gronemeyer H, Laudet V: Transcription factors 3: nuclear receptors. Protein Profile. 1995, 2: 1167-1322.Google Scholar
- Mangelsdorf DJ, Thummel C, Beato M, et al: The nuclear receptor superfamily: the second decade. Cell. 1995, 83: 835-839. 10.1016/0092-8674(95)90199-X.PubMedView ArticleGoogle Scholar
- Katzenellenbogen JA, Katzenellenbogen BS: Nuclear hormone receptors: ligand-activated regulators of transcription and diverse cell responses. Chem Biol. 1996, 3: 529-536. 10.1016/S1074-5521(96)90143-X.PubMedView ArticleGoogle Scholar
- Giguère V: Orphan nuclear receptors: from gene to function. Endocrine Rev. 1999, 20: 689-725. 10.1210/er.20.5.689.Google Scholar
- Beekman JM, Allan GF, Tsai SY, et al: Transcriptional activation by the estrogen receptor requires a conformational change in the ligand binding domain. Mol Endocrinol. 1993, 7: 1266-1274. 10.1210/me.7.10.1266.PubMedGoogle Scholar
- McDonnell DP, Clemm DL, Hermann T, et al: Analysis of estrogen receptor function in vitro reveals three distinct classes of anti-estrogens. Mol Endocrinol. 1995, 9: 659-669. 10.1210/me.9.6.659.PubMedGoogle Scholar
- Katzenellenbogen J, O'Malley BW, Katzenellenbogen BS: Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. Mol Endocrinol. 1996, 10: 119-131. 10.1210/me.10.2.119.PubMedGoogle Scholar
- Shibata H, Spencer TE, Onate SA, et al: Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action. Recent Prog Horm Res. 1996, 52: 141-165.Google Scholar
- Tora L, White J, Brou C, et al: The human estrogen receptor has two independent nonacidic activation functions. Cell . 1989, 59: 477-487.PubMedView ArticleGoogle Scholar
- Berry M, Metzger D, Chambon P: Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen. EMBO J. 1990, 9: 2811-2818.PubMedPubMed CentralGoogle Scholar
- Kraus WL, McInerney EM, Katzenellenbogen BS: Ligand-dependent transcriptionally productive association of the amino- and carboxy-terminal regions of a steroid hormone nuclear receptor. Proc Natl Acad Sci USA. 1995, 92: 12314-12318.PubMedPubMed CentralView ArticleGoogle Scholar
- McInerney EM, Katzenellenbogen BS: Different regions in activation function-1 of the human estrogen receptor required for antiestrogen- and estradiol-dependent transcription activation. J Biol Chem. 1996, 271: 24172-24178. 10.1074/jbc.271.39.24172.PubMedView ArticleGoogle Scholar
- Barkhem T, Carlsson B, Nilsson Y, et al: Differential response of estrogen receptor α and estrogen receptor β to partial estrogen agonists/antagonists. Mol Pharmacol . 1998, 54: 105-112., This is a very important paper demonstrating the differences in ligand binding specificities between HERa and ERβPubMedGoogle Scholar
- McInerney EM, Weis KE, Sun J, et al: Transcription activation by the human estrogen receptor subtype β (ERβ) studied with ERβ and ERα receptor chimeras. Endocrinology. 1998, 139: 4513-4522. 10.1210/en.139.11.4513.PubMedGoogle Scholar
- Danielian PS, White R, Lees JA, et al: Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J. 1992, 11: 1025-1033.PubMedPubMed CentralGoogle Scholar
- Henttu PMA, Kalkhoven E, Parker MG: AF-2 activity and recruitment of steroid receptor coactivator 1 to the estrogen receptor depend on a lysine residue conserved in nuclear receptors. Mol Cell Biol. 1997, 17: 1832-1839.PubMedPubMed CentralView ArticleGoogle Scholar
- Darimont BD, Wagner RL, Apriletti JW, et al: Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. 1998, 12: 3343-3356.PubMedPubMed CentralView ArticleGoogle Scholar
- Feng W, Ribeiro RC, Wagner RL, et al: Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science. 1998, 280: 1747-1749. 10.1126/science.280.5370.1747.PubMedView ArticleGoogle Scholar
- Mak HY, Hoare S, Henttu PM, et al: Molecular determinants of the estrogen receptor-coactivator interface. Mol Cell Biol. 1999, 19: 3895-3903.PubMedPubMed CentralView ArticleGoogle Scholar
- Brzozowski AM, Pike ACW, Dauter Z, et al: Molecular basis of agonism and antagonism in the estrogen receptor. Nature . 1997, 389: 753-758. 10.1038/39645., This is the first of two papers [38,39] revealing clear pictures of the LBD of estrogen receptors with their ligands. This is a much quoted and uniquely original study, demonstrating for the first time how the structure of the LBD of nuclear receptors (in this case, estrogen receptor a) is altered upon agonist/antagonist bindingPubMedView ArticleGoogle Scholar
- Pike ACW, Brzozowski AM, Hubbard RE, et al: Structure of the ligand-binding domain of oestrogen receptor β in the presence of a partial agonist and a full antagonist. The EMBO J . 1999, 18: 4608-4618. 10.1093/emboj/18.17.4608.PubMedView ArticleGoogle Scholar
- Paige LA, Christensen DJ, Gron H, et al: Estrogen receptor (ER) modulators each induce distinct conformational changes in ERα and ERβ. Proc Natl Acad Sci USA . 1999, 96: 3999-4004. 10.1073/pnas.96.7.3999.PubMedPubMed CentralView ArticleGoogle Scholar
- Paech K, Webb P, Kuiper GGJM, et al: Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science. 1997, 277: 1508-1510. 10.1126/science.277.5331.1508., This is an extremely important paper demonstrating, for the first time, that ERα and ERβ can have opposite effects in modulation of expression of genesPubMedView ArticleGoogle Scholar
- Conte FA, Grumbach MM, Ito Y, et al: A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450 arom). J Clin Endocrinol Metab. 1994, 78: 1287-1292. 10.1210/jc.78.6.1287.PubMedGoogle Scholar
- Morishima A, Grumbach MM, Simpson ER, et al: Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995, 80: 3689-3698. 10.1210/jc.80.12.3689.PubMedGoogle Scholar
- MacGillivray MH, Morishima A, Conte F, et al: Pedriatic endocrinology update: an overview. The essential roles of estrogens in pubertal growth, epiphyseal fusion and bone turnover: lessons from mutations in the genes for aromatase and the estrogen receptor. Horm Res . 1998, 49 (suppl 1): 2-8. 10.1159/000053061.View ArticleGoogle Scholar
- Masood S: Estrogen and progesterone receptors in cytology: a comprehensive review. Diagn Cytopathol. 1992, 8: 475-491.PubMedView ArticleGoogle Scholar
- Jordan VC: Molecular mechanisms of antiestrogen action in breast cancer. Breast Cancer Res Treat. 1994, 31: 41-52.PubMedView ArticleGoogle Scholar
- Osborne CK, Elledge RM, Fuqua SA: Estrogen receptors in breast cancer therapy. Sci Am. 1996, 32-41.Google Scholar
- Dotzlaw H, Leygue E, Watson PH, et al: Expression of estrogen receptor-β in human breast tumors. J Clin Endocrinol Metab. 1997, 82: 2371-2374. 10.1210/jc.82.7.2371.PubMedGoogle Scholar
- Leygue E, Dotzlaw H, Watson PH, et al: Expression of estrogen receptor β1, β2, and β5 messenger RNAs in human breast tissue. Cancer Res. 1999, 59: 1175-1179.PubMedGoogle Scholar
- Sasano H, Suzuki T, Matsuzaki Y, et al: Messenger ribonucleic acid in situ hybridization analysis of estrogen receptors α and β in human breast carcinoma. J Clin Endocrinol Metab. 1999, 84: 781-785. 10.1210/jc.84.2.781.PubMedGoogle Scholar
- Saji S, Jensen EV, Nilsson S, et al: Estrogen receptors α and β in the rodent mammary gland. Proc Natl Acad Sci USA. 2000, 97: 337-342. 10.1073/pnas.97.1.337., This study reveals, for the first time, the cellular expression and regulation of ERa and ERα in the rodent breast. The study reveals that epithelial cells that divide in the breast have neither estrogen receptorPubMedPubMed CentralView ArticleGoogle Scholar
- Dotzlaw H, Leygue E, Watson PH, et al: Estrogen receptor-β messenger RNA expression in human breast tumor biopsies: relationship to steroid receptor status and regulation by progestins. Cancer Res. 1999, 59: 529-532.PubMedGoogle Scholar
- Speirs V, Parkes AT, Kerin MJ, et al: Coexpression of estrogen receptor-α and -β: poor prognostic factors in human breast cancer?. Cancer Res. 1999, 59: 525-528., This paper should be read because it formulates an important question for which there are no answers at present because of the paucity of informationPubMedGoogle Scholar
- Lichtman R: Perimenopausal and postmenopausal hormone replacement therapy. Part 1. An update of the literature on benefits and risks. Nurse Midwifery. 1996, 41: 3-28. 10.1016/0091-2182(95)00082-8.View ArticleGoogle Scholar
- Lichtman R: Perimenopausal and postmenopausal hormone replacement therapy. Part 2. Hormonal regimens and complementary and alternative therapies. Nurse Midwifery. 1996, 41: 195-210. 10.1016/0091-2182(96)00020-1.View ArticleGoogle Scholar
- Saunders PTK, Maguire SM, Gaughan J, et al: Expression of oestrogen receptor (ERβ) in multiple rat tissues visualised by immunohistochemistry. J Endocrinol. 1997, 154: R13-R16.PubMedView ArticleGoogle Scholar
- Mäkelä S, Strauss L, Kuiper G, et al: Differential expression of estrogen receptors α and β in adult rat accessory sex glands and lower urinary tract. Mol Cell Endocrinol (in press).Google Scholar
- Chang WY, Prins GS: Estrogen receptor-β: implications for the prostate gland. Prostate. 1999, 40: 115-124. 10.1002/(SICI)1097-0045(19990701)40:2<115::AID-PROS7>3.0.CO;2-3., This paper must be read because it is clear that ERβ, and therefore estrogens, have a role in regulation of prostatic growth and developmentPubMedView ArticleGoogle Scholar
- Krege JH, Hodgin JB, Couse JF, et al: Generation and reproductive phenotypes of mice lacking estrogen receptor β . Proc Natl Acad Sci USA. 1998, 95: 15677-15682. 10.1073/pnas.95.26.15677.PubMedPubMed CentralView ArticleGoogle Scholar
- Lindsay R, Hart DM, Aitken JM, et al: Long-term prevention of post-menopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet. 1976, 1: 1038-1041. 10.1016/S0140-6736(76)92217-0.PubMedView ArticleGoogle Scholar
- Christiansen C: Hormonal prevention and treatment of osteoporosis -- state of the art 1990. J Steroid Biochem Mol Biol . 1990, 37: 447-449. 10.1016/0960-0760(90)90496-8.PubMedView ArticleGoogle Scholar
- Cauley JA, Seeley DG, Ensrud K, et al: Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1995, 122: 9-16.PubMedView ArticleGoogle Scholar
- Spelsberg TC, Subramaniam M, Riggs L, et al: The actions and interactions of sex steroids and growth factors/cytokines on the skeleton. Mol Endocrinol. 1999, 13: 819-828. 10.1210/me.13.6.819.PubMedView ArticleGoogle Scholar
- Komm BS, Terpening CM, Benz DJ, et al: Estrogen binding receptor mRNA and biological response in osteoblast-like osteosarcoma cells. Science. 1988, 241: 81-83.PubMedView ArticleGoogle Scholar
- Eriksen EF, Colvard DS, Berg NJ, et al: Evidence of estrogen receptors in normal human osteoblast-like cells. Science . 1988, 241: 84-86.PubMedView ArticleGoogle Scholar
- Hofbauer LC, Khosla S, Dunstan CR, et al: Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology. 1999, 140: 4367-4370. 10.1210/en.140.9.4367.PubMedGoogle Scholar
- Oursler MJ, Pederson L, Fitzpatrick L, et al: Human giant cell tumors of the bone (osteoclastomas) are estrogen target cells. Proc Natl Acad Sci USA. 1994, 91: 5227-5231.PubMedPubMed CentralView ArticleGoogle Scholar
- Onoe Y, Miyaura C, Ohta H, Nozawa S, Suda T: Expression of estrogen receptor β in rat bone. Endocrinology . 1997, 138: 4509-4512. 10.1210/en.138.10.4509.PubMedGoogle Scholar
- Arts J, Kuiper GGJM, Janssen JM, et al: Differential expression of estrogen receptors α and β mRNA during differentiation of human osteoblast SV-HFO cells. Endocrinology. 1997, 138: 5067-5070. 10.1210/en.138.11.5067.PubMedGoogle Scholar
- Stampfer MJ, Colditz GA: Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991, 20: 47-63. 10.1016/0091-7435(91)90006-P.PubMedView ArticleGoogle Scholar
- Nabulsi AA, Folsom AR, White A, et al: Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med. 1993, 328: 1069-1075. 10.1056/NEJM199304153281501.PubMedView ArticleGoogle Scholar
- Grodstein F, Stampfer MJ, Colditz GA, et al: Postmenopausal hormone therapy and mortality. N Engl J Med . 1997, 336: 1769-1775. 10.1056/NEJM199706193362501.PubMedView ArticleGoogle Scholar
- Nathan L, Chaudhuri G: Estrogens and atherosclerosis. Annu Rev Pharmacol Toxicol. 1997, 37: 477-515. 10.1146/annurev.pharmtox.37.1.477.PubMedView ArticleGoogle Scholar
- Mendelsohn ME, Karas RH: The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1997, 340: 1801-1811. 10.1056/NEJM199906103402306.Google Scholar
- Kim-Schulze S, McGowan KA, Hubchak SC, et al: Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial cells. Circulation. 1996, 94: 1402-1407.PubMedView ArticleGoogle Scholar
- Venkov CD, Rankin AB, Vaughan DE: Identification of authentic estrogen receptor in cultured endothelial cells: a potential mechanism for steroid hormone regulation of endothelial function. Circulation . 1996, 94: 727-733.PubMedView ArticleGoogle Scholar
- Karas RH, Patterson BL, Mendelsohn ME: Human vascular smooth muscle cells contain functional estrogen receptor. Circulation. 1994, 89: 1943-1950.PubMedView ArticleGoogle Scholar
- Register TC, Adams MR: Coronary artery and cultured aortic smooth muscle cells express mRNA for both the classical estrogen receptor and the newly described estrogen receptor β. J Steroid Biochem Mol Biol. 1998, 64: 187-191. 10.1016/S0960-0760(97)00155-6.PubMedView ArticleGoogle Scholar
- Lindner V, Kim SK, Karas RH, et al: Increased expression of estrogen receptor-β mRNA in male blood vessels after vascular injury. Circulation Res. 1998, 83: 224-229.PubMedView ArticleGoogle Scholar
- Grohé C, Kahlert S, Lobbert K, et al: Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett . 1997, 416: 107-112. 10.1016/S0014-5793(97)01179-4.PubMedView ArticleGoogle Scholar
- White MM, Zamudio S, Stevens T, et al: Estrogen, progesterone, and vascular reactivity: potential cellular mechanisms. Endocr Rev. 1995, 16: 739-751. 10.1210/er.16.6.739.PubMedGoogle Scholar
- Foegh ML, Ramwell PW: Cardiovascular effects of estrogen: implications of the discovery of the estrogen receptor subtype β. Curr Opin Nephr Hypertens. 1998, 7: 83-89. 10.1097/00041552-199801000-00014.Google Scholar
- Valverde MA, Rojas P, Amigo J, et al: Acute activation of Maxi-k channels (hSlo) by estradiol binding to the β subunit. Science. 1999, 285: 1929-1931. 10.1126/science.285.5435.1929.PubMedView ArticleGoogle Scholar
- Farhat MY, Abi-Younes S, Ramwell PW: Non-genomic effects of estrogen and the vessel wall. Biochem Pharmacol. 1996, 51: 571-576. 10.1016/S0006-2952(95)02159-0.PubMedView ArticleGoogle Scholar
- Kauser K, Rubanyi GM: Potential cellular signaling mechanisms mediating upregulation of endothelial nitric oxide production by estrogen. J Vascular Res. 1997, 34: 229-236.View ArticleGoogle Scholar
- Nuedling S, Kahlert S, Loebbert K, et al: Differential effects of 17 β-estradiol on mitogen-activated protein kinase pathways in rat car-diomyocytes. FEBS Lett. 1999, 454: 271-276. 10.1016/S0014-5793(99)00816-9.PubMedView ArticleGoogle Scholar
- Chen Z, Yuhanna IS, Galcheva-Gargova Z, et al: Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest. 1999, 103: 401-406.PubMedPubMed CentralView ArticleGoogle Scholar
- Mendelsohn ME, Karas RH: Estrogen and the blood vessel wall. Curr Opin Cardiol. 1994, 9: 619-626.PubMedView ArticleGoogle Scholar
- Farhat MY, Lavigne MC, Ramwell PW: The vascular protective effects of estrogen. FASEB J. 1996, 10: 615-624.PubMedGoogle Scholar
- Grohé C, Kahlert S, Lobbert K, et al: Expression of oestrogen receptor α and β in rat heart: role of local oestrogen synthesis. J Endocrinol. 1998, 156: R1-R7.PubMedView ArticleGoogle Scholar
- Mikkola T, Viinikka L, Ylikorkala O: Estrogen and postmenopausal estrogen/progestin therapy: effect on endothelium-dependent prostacyclin, nitric oxide and endothelin-1 production. Eur J Obstet Gynecol Reprod Biol. 1998, 79: 75-82. 10.1016/S0301-2115(98)00050-5.PubMedView ArticleGoogle Scholar
- Morey AK, Razandi M, Pedram A, et al: Oestrogen and progesterone inhibit the stimulated production of endothelin-1. Biochem J. 1998, 330: 1097-1105.PubMedPubMed CentralView ArticleGoogle Scholar
- Pinkerton JV, Santen R: Alternatives to the use of estrogen in post-menopausal women. Endocrine Rev. 1999, 20: 308-320. 10.1210/er.20.3.308.View ArticleGoogle Scholar
- Nickenig G, Baumer AT, Grohe C, et al: Estrogen modulates AT1 receptor gene expression in vitro and in vivo. Circulation. 1998, 97: 2197-2201.PubMedView ArticleGoogle Scholar
- Foegh ML, Khirabadi BS, Nakanishi T, et al: Estradiol protects against experimental cardiac transplant atherosclerosis. Transplant Proc. 1987, 19 (suppl 5): 90-95.Google Scholar
- Foegh ML, Asotra S, Howell MH, et al: Estradiol inhibition of arterial neointimal hyperplasia after balloon injury. J Vasc Surg. 1994, 19: 722-726.PubMedView ArticleGoogle Scholar
- Akishita M, Ouchi Y, Miyoshi H, et al: Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells. Atherosclerosis. 1997, 130: 1-10. 10.1016/S0021-9150(96)06023-6.PubMedView ArticleGoogle Scholar
- Scheuer J, Malhotra A, Schaible TF, et al: Effects of gonadectomy and hormonal replacement on rat hearts. Circ Res. 1987, 61: 12-19.PubMedView ArticleGoogle Scholar
- Malhotra A, Buttrick P, Scheuer J: Effects of sex hormones on development of physiological and pathological cardiac hypertrophy in male and female rats. Am J Physiol. 1990, 259: H866-H871.PubMedGoogle Scholar
- Iafrati MD, Karas RH, Aronovitz M, et al: Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nat Med. 1997, 3: 545-548., See PubMedView ArticleGoogle Scholar
- Lindner V, Kim SK, Karas RH, et al: Increased expression of estrogen receptor-beta mRNA in male blood vessels after vascular injury. Circulation Res. 1998, 83: 224-229., See PubMedView ArticleGoogle Scholar
- Karas RH, Hodgin JB, Kwoun M, et al: Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice. Proc Natl Acad Sci USA. 1999, 96: 15133-15136. 10.1073/pnas.96.26.15133., These three papers [100–102] form an important series of papers about the roles of the two estrogen receptors in the vessel wall. They are particularly interesting studies because we do not now have, but are in the process of obtaining, answers to this important questionPubMedPubMed CentralView ArticleGoogle Scholar
- McEwen BS, Alves SE: Estrogen actions in the central nervous system. Endocrine Rev. 1999, 20: 279-307. 10.1210/er.20.3.279.Google Scholar
- Simerly RB, Chang C, Muramatsu M, et al: Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol. 1990, 294: 76-95.PubMedView ArticleGoogle Scholar
- Shughrue PJ, Lane MV, Merchenthaler I: Comparative distribution of estrogen receptor-α and -β mRNA in the rat central nervous system. J Comp Neurol. 1997, 388: 507-525. 10.1002/(SICI)1096-9861(19971201)388:4<507::AID-CNE1>3.0.CO;2-6.PubMedView ArticleGoogle Scholar
- Shughrue PJ, Lubahn DB, Negro-Vilar A, et al: Responses in the brain of estrogen receptor α-disrupted mice. Proc Natl Acad Sci USA. 1997, 94: 11008-11012. 10.1073/pnas.94.20.11008.PubMedPubMed CentralView ArticleGoogle Scholar
- Laflamme N, Nappi RE, Drolet G, et al: Expression and neuropeptidergic characterization of estrogen receptors (ERα and ERβ) throughout the rat brain: anatomical evidence of distinct roles of each subtype. J Neurobiol. 1998, 36: 357-378. 10.1002/(SICI)1097-4695(19980905)36:3<357::AID-NEU5>3.3.CO;2-U.PubMedView ArticleGoogle Scholar
- Kuiper GGJM, Shughrue PJ, Merchenthaler I, et al: The estrogen receptor β subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroendocrinol. 1998, 19: 253-286. 10.1006/frne.1998.0170.PubMedView ArticleGoogle Scholar
- Moffatt CA, Rissman EF, Shupnik MA, et al: Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-β gene-disrupted mice. J Neurosci. 1998, 18: 9556-9563.PubMedGoogle Scholar
- Shughrue PJ, Lane MV, Merchenthaler I: Autoradiographic evidence for the binding of 125I-estrogen to estrogen receptor-β (ERβ) in the wild type and ERα-knockout (ERαKO) mouse brain [abstract 734.13]. Soc Neurosci Abstr. 1998, 24: 1849-Google Scholar
- Shughrue PJ, Lane MV, Merchenthaler I: Biologically active estrogen receptor-β: evidence from in vivo autoradiographic studies with estrogen receptor α-knockout mice. Endocrinology. 1999, 140: 2613-2620. 10.1210/en.140.6.2613.PubMedGoogle Scholar
- Couse JF, Korach KS: Estrogen receptor null mice: what have we learned and where will they lead us?. Endocrine Rev. 1999, 20: 358-417. 10.1210/er.20.3.358.View ArticleGoogle Scholar
- Mitchner NA, Garlick C, Ben-Jonathan N: Cellular distribution and gene regulation of estrogen receptors α and β in the rat pituitary gland. Endocrinology. 1998, 139: 3976-3983. 10.1210/en.139.9.3976.PubMedGoogle Scholar