Estrogen receptors

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The estrogen receptor (ER) is the receptor of estrogens like estradiol. Agonists of the ER include estradiol, ethinylestradiol, and conjugated estrogens. Partial agonists of the ER, or selective estrogen receptor modulators, include tamoxifen, clomifene, and raloxifene. Antagonists of the ER include fulvestrant.

There are two different forms of the estrogen receptor, ERα and ERβ. ERβ may have anti-proliferative effects that oppose the effects of ERα.[1]

Regulation[edit]

In MCF-7 breast cancer cells, administration of estradiol suppressed estrogen receptor α (ERα) levels by about 60% after 6 hours. ERα mRNA expression was transiently decreased by about 90%. ERα expression returned to normal in 24-48 hours.[2] ERα gene transcription was suppressed by 90% after 1 hour, then increased to 2x its original rate after 3-6 hours, remaining elevated for at least 48 hours. This suggests that downregulation of ERα by estradiol occurs both at transcription and post-transcription.[2]

Tamoxifen did not upregulate or downregulate ERα. When administered concurrently with estradiol, it prevented the downregulation of ERα by estradiol.[2][3]

The following table summarizes the regulatory effects of various agents on ERα:

Drug Class Tissue/cell line Environment ERα mRNA ERα Refs
Estradiol ER agonist MCF-7a, endothelium in vitro + [4]f[2][3]
Hypothalamus + + [4]f
Osteoblast + [4]f
Breast (primate) in vivo + [5]
Fulvestrant SERD MCF-7a in vitro ± [4]f
Tamoxifen SERM MCF-7a in vitro ± [4]f
Uterus [4]f
Breast (primate) in vivo [5]
Raloxifene SERM MCF-7a in vitro + [4]f
Estradiol + testosterone ER agonist + AR agonist Breast (primate) in vivo ±d [5]
Estradiol + progesterone ER agonist + PR agonist Breast (primate) in vivo +e [5]
ORG-2058 PR agonist T47Da in vitro [4]f
Promegestone PR agonist T47Da, MCF-7a in vitro [4]f
Mifepristone PR antagonist T47Da in vitro + [6]
uterus in vivo + [7]
Danazol PBMCb (human, rabbit) in vivo [8][9]
Flutamide + GnRH agonistc AR antagonist + GnRH agonist Prostate in vivo + [10]
Calcitriol Vitamin D3 MCF-7a in vitro [4]f
hCG Gonadotropin MCF-7a in vitro [4]f
GnRH GnRH agonist Ovary in vitro [4]f

a Breast cancer cell line.
b Peripheral blood mononuclear cell.
c Paper does not specify which GnRH agonist was used.
d Comparing with the effect of estradiol alone, this suggests that testosterone alone would result in a decrease of ERα mRNA expression.
e The increase in mRNA expression with estradiol and progesterone is less than the increase with estradiol alone, suggesting that progesterone alone inhibits ERα mRNA expression. This hypothesis is supported by the effect of other progestogens on ERα mRNA expression.
f This review article has errors. In particular, it omitted that the patients who were taking flutamide were also taking a GnRH agonist. TODO: Check the references in Table 1 and replace them with the original articles cited in the review.

References[edit]

  1. Weihua Z, Saji S, Mäkinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA (2000). "Estrogen receptor (ER) β, a modulator of ERα in the uterus". Proc. Natl. Acad. Sci. U.S.A.. 97 (11): 5936–41. doi:10.1073/pnas.97.11.5936. PMC 18537. PMID 10823946.
  2. 2.0 2.1 2.2 2.3 Mary Beth Martin et al (1993). "Regulation of Estrogen Receptor Expression in Breast Cancer". {{{journal}}}. 330 ({{{issue}}}): 143–153. doi:10.1007/978-1-4615-2926-2_11. PMID 8368130. ISSN 0065-2598.
  3. 3.0 3.1 John J Pink et al (1996). "Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines". {{{journal}}}. 56 ({{{issue}}}): 2321–2330. PMID 8625307.
  4. 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 J. J. Pinzone et al (2004). "Molecular and Cellular Determinants of Estrogen Receptor Expression". Molecular and Cellular Biology. 24 (11): 4605–4612. doi:10.1128/MCB.24.11.4605-4612.2004. PMC 416410. PMID 15143157. ISSN 0270-7306.
  5. 5.0 5.1 5.2 5.3 Jian Zhou et al (2000). "Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression". The FASEB Journal. 14 (12): 1725–1730. doi:10.1096/fj.99-0863com. ISSN 0892-6638.
  6. G. Savoldi et al (1995). "Progesterone agonists and antagonists induce down– and up–regulation of estrogen receptors and estrogen inducible genes in human breast cancer cell lines". The International Journal of Biological Markers. 10 (1): 47–54. doi:10.1177/172460089501000109. ISSN 1724-6008.
  7. O Mäentausta et al (1993). "The effects of an antiprogestin, mifepristone, and an antiestrogen, tamoxifen, on endometrial 17 beta-hydroxysteroid dehydrogenase and progestin and estrogen receptors during the luteal phase of the menstrual cycle: an immunohistochemical study.". The Journal of Clinical Endocrinology & Metabolism. 77 (4): 913–918. doi:10.1210/jcem.77.4.8408465. ISSN 0021-972X.
  8. Jiro Fujimoto et al (1995). "Danazol decreases transcription of estrogen receptor gene in human monocytes". General Pharmacology: The Vascular System. 26 (3): 507–516. doi:10.1016/0306-3623(94)00227-E. ISSN 03063623.
  9. T. Tamaya et al (1991). "Different Effects on Oestrogen Binding Sites and Anti-Oestrogenic Action of Danazol and Progesterone". Annals of Clinical Biochemistry: An international journal of biochemistry and laboratory medicine. 28 (3): 250–252. doi:10.1177/000456329102800309. ISSN 0004-5632.
  10. Inge G. Kruithof-Dekker et al (1996). "Elevated Estrogen Receptor Expression in Human Prostatic Stromal Cells by Androgen Ablation Therapy". Journal of Urology. 156 (3): 1194–1197. doi:10.1016/S0022-5347(01)65749-5. PMID 8709345. ISSN 0022-5347.