REVIEWS Development of subtype-selective oestrogen receptor-based therapeutics Stefan Nilsson*‡, Konrad F. Koehler* and Jan-Åke Gustafsson‡§ Abstract | The two oestrogen receptor subtypes α and β are hormone-regulated modulators of intracellular signalling and gene expression. Regulation of oestrogen receptor activity is crucial not only for development and homeostasis but also for the treatment of various diseases and symptoms. Classical selective oestrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging data suggest that the development of subtype-selective ligands that specifically target either oestrogen receptor-α or oestrogen receptor-β could be a more optimal approach for the treatment of cancer, cardiovascular disease, multiple sclerosis and Alzheimer’s disease. Detrusor muscle Oestrogen receptors (ERs) are intracellular transcription For example, the expression of ERα but not ERβ fluctuates Bladder muscle that relaxes to factors whose activity is modulated by the naturally depending on the stage of rat mammary gland develop- fill the bladder with urine or occurring oestrogens in the body or by synthetic, ment, going from relatively high levels at prepubertal stage contracts to squeeze urine out non-steroidal, non-hormonal agonist and antagonist to very low levels at pregnancy and then back up to high from the bladder. ligands. Oestrone (E1), oestradiol (E2; also known as levels during lactation, followed by a dramatic decrease 17β‑oestradiol) and oestriol (E3) are the three main at the postlactation stage4. During tumour progression endogenous oestrogens, of which E2 is the predomi- in invasive breast carcinoma, the expression of ERβ nant and most biologically active. E2 is produced from decreases compared with normal mammary tissue5, and testosterone by the aromatase enzyme cytochrome P450 oestrogen deficiency in the female rat leads to degenera- 19A1 (REF. 1). The primary sites of E2 production are the tion of the bladder ultra structure owing to an increased ovaries in women of fertile age and extragonadal tissues ratio of ERα to ERβ in the detrusor muscle; however, E2 (adipose tissue, brain, vascular endothelial cells, bone supplementation resulted in a significant increase in ERβ cells, breast tissue and skin fibroblasts) in postmeno­ expression and bladder function6. Whole-body glucose pausal women. In men, E2 is produced by the testes and intolerance induced by high-fat diet in female rats was extragonadal tissues. The physiological role of oestro- associated with decreased ERα expression in adipose gens includes sexual maturation and fertility, regulation tissue7, and in the mouse central nervous system, the of lipid and carbohydrate metabolism, skeletal develop- level of cytoplasmic ERα or ERβ in the dorsal hippocam- ment and integrity, and homeostasis of the cardiovascular pal region varied with the oestrous cycle8. Furthermore, *Karo Bio AB, Novum, and central nervous systems. in synapses of the rat hippocampal CA1 region, both SE‑141 57 Huddinge, Sweden. Today, we are aware of the existence of two ER ERα and ERβ decreased with age but, in contrast to ‡ Department of Biosciences subtypes; ERα, which is encoded by the ESR1 gene on ERα, the expression of ERβ increased in response to E2 and Nutrition, Karolinska 9 Institutet, Novum, chromosome 6, and ERβ, which is encoded by the ESR2 in older animals . SE‑141 83 Huddinge, gene on chromosome 14. Both subtypes are expressed Phenotypic characterization of knockout mice defi- Sweden. in a wide range of tissues and cell types throughout the cient in either the expression of ERα or ERβ has revealed §Center for Nuclear body; ERα has been found predominantly in bone, male interesting differences between the physiological roles Receptors and Cell Signalling, Department of Biology and reproductive organs (testes and epididymis), prostate of the two receptor subtypes (Supplementary informa- Biochemistry, University (stroma), uterus, ovary (thecal cells), liver, mammary tion S1 (table)). ERα has a more profound effect on of Houston, Houston, gland, adipose tissue, heart, vascular system and brain. the development and function of the mammary gland Texas 77204‑5056, USA. ERβ is mainly present in the bladder, prostate (epithelium), and uterus and on the maintenance of metabolic and Correspondence to J.-Å.G. ovary (granulosa cells), colon, adipose tissue, immune skeletal homeostasis. ERβ, however, has more pro- e‑mail: [email protected] 2,3 doi:10.1038/nrd3551 system, heart, vascular system, lung and brain . The nounced effects on the central nervous system and on Published online presence of ERα or ERβ has been shown to vary in differ­ conditions of cellular hyperproliferation. Both receptors 16 September 2011 ent tissues during development, ageing or disease state. have important roles in the development and function 778 | OCTOBER 2011 | VOLUME 10 www.nature.com/reviews/drugdisc © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Progestagen of the ovaries and in the protection of the cardiovascular fact decreases cardiovascular disease risk in women if Collective name for a ligand of system. More knowledge of the nature of ER subtype- MHT is initiated soon after menopause or before the the progesterone receptor, selective ligands (whether they are agonists or antago- age of 60 years11–13. The WHI results and conclusions such as progestogen, gestagen nists) and the biological roles of ERα or ERβ in different caused, however, a dramatic drop in the prescriptions for or progesterone. tissues could be used to decide which ER subtype to and use of MHT in the United States14 and worldwide15 target for the optimal treatment of various diseases and and an increased interest in the development of ER symptoms. E2 and classical selective oestrogen receptor subtype-selective modulators because of their poten- modulators (SERMs) target both of the ER subtypes, but tial to retain the benefits of MHT without the severe targeting just one subtype may lead to a more efficacious adverse events. therapy with less risk of side effects (BOX 1). ERα and ERβ regulate different classes of genes by A decline in oestrogen production in women as a binding to different sites on DNA and by the recruitment result of ceasing ovarian function during menopausal of different co-regulatory and chromatin remodelling transition substantially increases the risk of osteoporotic proteins16. ERβ-selective agonists can be divided into fractures and coronary heart disease (CHD), and can two major classes: those that are affinity and potency cause symptoms such as hot flushes and vaginal atrophy. selective for ERβ and those that are ERβ efficacy selec- During the 1990s, menopausal hormone therapy (MHT) tive16. ERβ-selective agonists do not stimulate the pro- — which primarily consisted of conjugated equine oes- liferation of breast or endometrial tissues. By contrast, trogens (CEEs) in combination with medroxyprogester- activation of ERα with the ERα-selective agonist pro- one acetate (MPA; a progestagen to prevent the risk for pyl pyrazole triol (PPT) is associated with proliferative endometrial cancer development) — was frequently responses in breast and uterine tissues17,18. Thus, selec- prescribed for treatment of menopausal symptoms, tive agonist activation of ERα imposes increased risk for prevention of postmenopausal bone loss and bone frac- the development of breast or endometrial cancer, which ture risks, and prevention of the development of CHD. makes the design and synthesis of ERα-selective agonists However, a study published by the Women’s Health a less-attractive approach for development of novel thera- Initiative (WHI) stated that combined oestrogen and pies. However, development of ERα-selective antagonists progestagen therapy should not be initiated or continued or ERα-selective ligands with mixed tissue selective ago- for the prevention of CHD owing to lack of efficacy to nist/antagonist activity (ERα-selective SERMs) may hold prevent cardiovascular events and increased risk of breast therapeutic promise (BOX 1). cancer10. It was stated that the overall health risks with In this article, we review the roles of ERα and ERβ in combined MHT exceeded its benefits10. The conclusions various animal disease models with a focus on the thera­ drawn from the WHI study have been widely discussed peutic opportunities of agonists that selectively target and criticized; the beneficial or detrimental effects of the ERβ subtype for treatment of cancer, cardiovascular MHT on cardiovascular outcome have been suggested disease, multiple sclerosis and Alzheimer’s disease. to depend on timing. Follow-up studies in women aged between 50 and 59 clearly showed that MHT in ER signalling and mechanism of action ER architecture. Both ER subtypes have a modular domain structure that is common to all members of Box 1 | SERMs and ER subtype-selective modulators the nuclear hormone receptor family19,20 (FIG. 1a). This domain structure consists of an amino-terminal activa- The acronym SERM (selective oestrogen receptor modulator) was coined in the early tion function 1 (AF1) domain for ligand-independent 1990s, before knowledge of the existence of two oestrogen receptor (ER) subtypes, and so it refers to a set of anti-oestrogenic ligands (for example, tamoxifen and raloxifene) activation of transcription, a central DNA binding with mixed, tissue-selective agonist and antagonist activity. This type of ligand displays domain (DBD) for sequence-specific