Terpenoids Found in the Umbelliferae Family Act as Agonists/Antagonists for ERα and ERβ: Differential Transcription Activity between Ferutinine-Liganded ERα and ERβ
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Estrogen receptor alpha
Estrogen receptor beta
Fulvestrant
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Hormone-dependent estrogen receptor (ER)-positive breast cancer cells may adapt to low estrogen environments such as produced by aromatase inhibitors. In many instances, cells become insensitive to the effects of estrogen but may still retain dependence on ER. We have investigated the expression, function, and activation of ERalpha in two endocrine-resistant MCF-7 models to identify mechanisms that could contribute to resistance. While MCF-7/LCC1 cells are partially estrogen dependent, MCF-7/LCC9 cells are fully estrogen insensitive and fulvestrant and tamoxifen resistant. In both MCF-7/LCC1 and MCF-7/LCC9 cell lines, high expression of ERalpha was associated with enhanced binding to the trefoil factor 1 (TFF1) promoter in the absence of estrogen and increased transcription of TFF1 and progesterone receptor. In contrast to the observations derived from hypersensitive and supersensitive models, these cells were truly estrogen independent; nevertheless, removal of ERalpha by siRNA, or fulvestrant, a specific ER downregulator, inhibited growth indicating dependence on ERalpha. In the absence of estrogen, neither ERalpha Ser118 nor Ser167 were phosphorylated as frequently found in other ligand-independent cell line models. Addition of estrogen activated ERalpha Ser118 in MCF-7 and LCC1 cells but not in LCC9 cells. We suggest that the estrogen-independent growth within these cell lines is accounted for by high levels of ERalpha expression driving transcription and full estrogen independence explained by lack of ERalpha activation through Ser118.
Fulvestrant
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Raloxifene
Estrogen receptor beta
Hormone response element
Estrogen receptor alpha
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The existence of two rather than one estrogen receptor, today characterized as estrogen receptor α (ERα) and estrogen receptor β (ERβ), indicates that the mechanism of action of 17β-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERβ is high compared with those amino acid residues in ERα LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17α-ethynyl,17β-estradiol, for example, has an ERα-selective agonist potency and that 16β,17α-epiestriol has an ERβ-selective agonist potency. We also report that genistein has an ERβ-selective affinity and potency but an ERα-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERα-selective partial agonist/antagonist function but a pure antagonist effect through ERβ. In addition, raloxifene displayed an ERα-selective antagonist potency, in agreement with its ERα-selective affinity. However, although ICI 164,384 showed an ERβ-selective affinity, it had a similar potency to antagonize the effect of 17β-estradiol in the ERα- and ERβ-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERβ is probably more different from that of ERα than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with betterin vivo efficacy and side effect profile than current available drugs.
Estrogen-related receptor gamma
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The incidence of osteoporosis and of cardiovascular disease increases in women after menopause. Although theses diseases can be prevented by estrogen replacement therapy, this treatment is associated with an increased risk of endometrial cancer and perhaps also with an increased risk of breast cancer. Thus, a therapy that could prevent postmenopausal bone loss and lower serum cholesterol concentrations without stimulating reproductive tissues would be desirable. Selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, produce beneficial estrogen-like effects on bone and lipid metabolism, while antagonizing estrogen in reproductive tissue. Both agonist and antagonist activities are mediated via high affinity interaction with the estrogen receptor (ER). Both types of ER (alpha and beta) may be involved in the mechanism by which SERMs produce tissue-selective pharmacology. This review will discuss the roles of ER alpha and ER beta in novel signal transduction pathways.
Raloxifene
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Estrogen receptor (ER) plays important roles in gene transcription and the proliferation of ER positive breast cancers. Selective modulation of ER has been a therapeutic target for this specific type of breast cancer for more than 30 years. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have been demonstrated to be effective therapeutic approaches for ER positive breast cancers. Unfortunately, 30–50% of ER positive tumors become resistant to SERM/AI treatment after 3–5 years. Fulvestrant, the only approved selective estrogen receptor degrader (SERD), is currently an important therapeutic approach for the treatment of endocrine-resistant breast cancers. The poor pharmacokinetic properties of fulvestrant have inspired the development of a new generation of oral SERDs to overcome drug resistance. In this review, we describe recent advances in ERα structure, functions, and mechanisms of endocrine resistance and summarize the development of oral SERDs in both academic and industrial areas.
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The recent discovery of a second estrogen receptor subtype, estrogen receptor-beta, may significantly advance our understanding of tissue specific effects of estrogenic compounds, both natural and synthetic. Although specific effects mediated by estrogen receptor beta in vivo remain to be elucidated, hypothetically the existence of two estrogen receptor subtypes (differing in both tissue distribution and biological activity) may help to explain the curious pharmacological behaviour of many estrogenic and antiestrogenic compounds, including the naturally occurring dietary phytoestrogens.
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