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 ERα mRNA ERα Refs
Estradiol ER agonist MCF-7a, endothelium + [4][2][3]
Hypothalamus + + [4]
Osteoblast + [4]
Breast (primate) + [5]
Fulvestrant SERD MCF-7a ± [4]
Tamoxifen SERM MCF-7a ± [4]
Uterus [4]
Breast (primate) [5]
Raloxifene SERM MCF-7a + [4]
Estradiol + testosterone ER agonist + AR agonist Breast (primate) ±d [5]
Estradiol + progesterone ER agonist + PR agonist Breast (primate) +e [5]
ORG-2058 PR agonist T47Da [4]
Promegestone PR agonist T47Da, MCF-7a [4]
Mifepristone PR antagonist T47Da, uterus + [4]
Danazol PBMCb [4]
Flutamide AR antagonist Prostate + [4]
Calcitriol Vitamin D3 MCF-7a [4]
hCG Gonadotropin MCF-7a [4]
GnRH GnRH agonist Ovary c c [4]

a Breast cancer cell line. b Peripheral blood mononuclear cell. c Ovarian tissue studied in isolation; HPG axis is not taken into account. 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.

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 4.12 4.13 4.14 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.