Estradiol receptors

Hormone antagonists (tamoxifen and toremifen bind to the estradiol receptor, flutamide binds to the androgen receptor) are used for treating breast and prostate cancer. 

Hormone receptors for steroids were discovered in the early 1960s, when the technology to radioactively mark steroids became available. By obtaining tritium-labeled estradiol, Jensen could show the existence of an intracellular protein component that bound specifically to this hormone and that was called the estradiol receptor (ER). 

Redeuilh G, Mon charm ont B, Secco C, Baulieu EE (1987) Subunit composition of the molybdate stabilized 8-9S nontransformed estradiol receptor purified from calf uterus. J Biol Chem 262 6969... 

Childs GV, Unabia G, Komak S (2001) Differential expression of estradiol receptors alpha and beta by gonadotrophs during the estrous cycle. J Histochem Cytochem 49 665-666... 

Meyers CY, Kolb VM, Gass GH, et al. 1988. Doisynolic-type acids - uterotropically potent estrogens which compete poorly with estradiol for cytosolic estradiol receptors. J Steroid Biochem 31 (4A) 393-404. 

Williams J, Eckols K, Uphouse L. 1989b. Estradiol and chlordecone interactions with the estradiol receptor. Toxicol Appl Pharmacol 98 413-421. 

Estrogens act by interacting with the specific estradiol receptors in the cytoplasm of the target cells and mediate the transcription of the relevant mRNA by attaching itself to the appropriate gene. 

Bignon, E., Pons, M., Crastes de Depaulet, A.C., Dore, J.C., Gilbert, J., Abecassis, J., Miquel, J.F., Ojasoo, T. and Raynaud, J.P. (1989) Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast... 

Figure 6.28 Metabolism of diethylstilboestrol via an epoxide intermediate. This potentially reactive intermediate may show an affinity for the estradiol receptor and thereby accumulate in oestrogen target organs. This may facilitate reaction with DNA in these organs. Source. From Ref. 10.

Tezak, Z., B. Simic, and J. Kniewald (1992). Effect of pesticides on estradiol receptor complex formation in rat uterus cytosol. Fund Chem. Toxicol., 30 879-885. 

Bignon E, Pons M, Crastes de Paulet A, Dore JC, Gilbert J, Abecassis J, Miquel JF, Ojasoo T, Raynaud JP (1989) Effect of triphenylacrylonititrile derivatives on estradiol-receptor binding and on human breast cancer cell growth. J Med Chem 32 2092-2103... 

Vessieres A, Top S, Vaillant C, Osella D, Momon JP, Jaouen G (1992) Estradiol modified by metal carbonyl clusters as suicide substrates for the study of receptor proteins application to the estradiol receptor. Angew Chem Int Ed Engl 31 753-755... 

Top S, Vessieres A, Jaouen G (1994) Synthetic strategy for organometallic complexes of rhenium with exceptionally high affinity for the estradiol receptor. Their potential use as imaging and therapeutic agents. J Chem Soc Chem Commun 4 453 154... 

Top S, El Hafa H, Vessieres A, Quivy J, Vaissermann J, Huges DW, McGlinchey MJ, Momon JP, Thoreau E, Jaouen G (1995) Rhenium carbonyl complexes of 0-estradiol derivatives with high affinity for the estradiol receptor an approach to selective organometallic radiopharmaceuticals. J Am Chem Soc 117 8372-8380... 

Schneider MR, Von Angerer E, Schonenberger H, Michel RT, Fortmeyer HP (1982) 1, 1, 2-triphenylbut-l-enes relationship between structure, estradiol receptor affinity, and mammary tumor inhibiting properties. J Med Chem 25 1070-1077... 

Scheme 22 Differently labelled estradiols with attached organometallic rhenium moieties. RBA is the relative binding affinity to the estradiol receptor...

The bis-Cp titanium molecules shown in Scheme 765 have been synthesized and used as potential antiestrogenic vectors to the estradiol receptor and a recognized cytotoxic molecule. They also proved to be particularly easy to exchange with Re in order to prepare organometallic radiopharmaceutical compounds with antiestrogenic properties.2020 These processes have been used as a source for Re(CO)3 through thermal ligand-transfer reaction between Cp titanium complexes and Re2(CO)i0. 

Bucourt, R., Vignau, M. and Torelli, V. (1978) New biospecific adsorbents for the purification of estradiol receptor. The Journal of Biological Chemistry, 253, 8221-8228. 

Migliaccio, A., Castoria, G., Di Domenico, M., Falco, A., Bilancio, A., Lombardi, M., Barone, M. V., Ametrano, D., Zannini, M. S., Abbondanza, C., and Auricchio, F. 2000. Steroid-induced androgen receptor-estradiol receptor (3-src complex triggers prostate cancer cell proliferation. EMBO J. 19 5406-17. 

Ateache V, RATAjezAK T Senaei S and Hahnel R (1985) Purification of Molybdate-stabilized 9-10 S estradiol receptor from calf uterus. J Biol Chem 260 5936-5941. 

Unfortunately, a third of hormone-dependent tumors do not respond to tamoxifen and another third acquire resistance. In order to overcome these deficiencies, several platinum complexes derived from estradiol, estrone, or the synthetic estrogen hexestrol were prepared as estradiol receptors. These compounds proved to be similar in activity to... 

The complexes with the shortest dimethyl amino side chains (n = 2, 3, or 4) retain the best affinity for the two forms of the estradiol receptor. On MCF7 hormone-dependent breast cancer cells, the anti-proliferative effect of these complexes at molarities of 1 xM is slightly stronger than that of OH-Tam for complexes where = 3 and 5 3b and 3d, and this effect is not completely suppressed by addition of estradiol. This seems to indicate that the observed anti-proliferative effect is the combination of an antihormonal effect linked to the tamoxifen skeleton and mediated by the estradiol receptor, and a cytotoxic effect induced by the presence of the ferrocenyl substituent. In fact, the cytotoxic properties of the ferricinium cation (Fc ), which is easily formed by oxidation in biological media, are well known.It should however be noted that ferrocene alone has no effect despite being able to enter cells without difficulty. 

Top, S., El Hafa, H., Vessieres, A., Quivy, J., Vaisseraiann, J., Hughes, D. W., McGlinchey, M. J., Momon, J.-P., Thoreau, E., Jaouen, G. (1995). Rhenium carbonyl complexes of 3-estradiol derivatives with high affinity for the estradiol receptor An approach to selective organometallic radiopharmaceuticals, J. Am. Chem. Soc., 117 8372. 

Swaneck, G. E., and Fishman, J., Covalent binding of the endogenous estrogen 16a-hydroxyestrone to estradiol receptor in human breast cancer cells Characterization and intranuclear localization. Proc. Natl. Acad. Sci. USA 85,7831-7835 (1988). 

Kumar SA, Beach TA, Dickerman HW 1980. Specificity of oligodeoxynucleotide binding of mouse uterine cytosol estradiol receptors. Proc Natl Acad Sci USA 77(6) 3341-3345. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC 1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669) 806-811. 

Equally important is the high affinity binding of the Tc-estradiol analog to the estradiol receptor. The functional group chosen must not interfere with this binding and must be attached to the estradiol molecule at a point which does not interfere with binding to the receptor. The ability of the Tc-compound to... 

Figure 4. Conceptual representation of a bifunctional Tc radiopharmaceutical for imaging estradiol receptors...

Wiebe, J.P., and K.J. Barr. 1988. Effect of prenatal and neonatal exposure to lead on the affinity and number of estradiol receptors in the uterus. J. Toxicol. Envirorr Health 24(4) 451 0. 

---