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More Stable, More Estrogenic: The SERM-ERα LBD Complex

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DOI: 10.4236/jbpc.2011.23029    3,764 Downloads   7,157 Views   Citations

ABSTRACT

Many synthetic selective estrogen receptor modulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation of the LBD, most SERMs display different ligand-dependent pharmacological profiles. We show here that increased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihydrobenzoxathiin-based SERMs using molecular modelling techniques. Analyses of tamoxifen (TAM) and 4-hydroxytamoxifen (OHT) in complex with the LBD furthermore indicates that the conversion of TAM to OHT increases both the affinity to ERα and the partial agonism of the anti-cancer drug, which provides a plausible explanation of the counterintuitive results of TAM therapy.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Gao, L. , Tu, Y. and Eriksson, L. (2011) More Stable, More Estrogenic: The SERM-ERα LBD Complex. Journal of Biophysical Chemistry, 2, 233-243. doi: 10.4236/jbpc.2011.23029.

References

[1] Riggs, B.L. and Hartmann, L.C. (2003) Drug therapy: Selective estrogen-receptor modulators—Mechanisms of action and application to clinical practice. New England Journal of Medicine, 348, 618-629. doi:10.1056/NEJMra022219
[2] Clarke, M., Collins, R., Davies, C., Godwin, J., Gray, R., Peto, R. and Grp, E.B.C.T.C. (1998) Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet, 351, 1451-1467. doi:10.1016/S0140-6736(97)11423-4
[3] Jordan, V.C. (2003) A most unlikely pioneering medicine. Nature Reviews Drug Discovery, 2, 205-213. doi:10.1038/nrd1031
[4] Sato, M., Rippy, M.K. and Bryant, H.U. (1996) Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB Journal, 10, 905-912.
[5] Assikis, V.J., Neven, P., Jordan, V.C. and Vergote, I. (1996) A realistic clinical perspective of tamoxifen and endometrial carcinogenesis. European Journal of Cancer, 32A, 1464-1476. doi:10.1016/0959-8049(96)00184-0
[6] Jin, Y., Desta, Z., Stearns, V., Ward, B., Ho, H., Lee, K. H., Skaar, T., Storniolo, A.M., Li, L., Araba, A., Blanchard, R., Nguyen, A., Ullmer, L., Hayden, J., Lemler, S., Weinshilboum, R.M., Rae, J.M., Hayes, D.F. and Flockhart, D.A. (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. Journal of the National Cancer Institute, 97, 30-39. doi:10.1093/jnci/dji005
[7] Desta, Z., Ward, B.A., Soukhova, N.V. and Flockhart, D.A. (2004) Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6. Journal of Pharmacology and Experimental Therapeutics, 310, 1062-1075. doi:10.1124/jpet.104.065607
[8] Seth, P., Lunetta, K.L., Bell, D.W., Gray, H., Nasser, S.M., Rhei, E., Kaelin, C.M., Iglehart, D.J., Marks, J.R., Garber, J.E., Haber, D.A. and Polyak, K. (2000) Phenol sulfotransferases: Hormonal regulation, polymorphism, and age of onset of breast cancer. Cancer Research, 60, 6859-6863.
[9] Falany, C.N., Wheeler, J., Oh, T.S. and Falany, J.L. (1994) Steroid sulfation by expressed human cytosolic sulfotransferases. Journal of Steroid Biochemistry and Molecular Biology, 48, 369-375. doi:10.1016/0960-0760(94)90077-9
[10] Shiau, A.K., Barstad, D., Loria, P.M., Cheng, L., Kushner, P.J., Agard, D.A. and Greene, G.L. (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell, 95, 927-937. doi:10.1016/S0092-8674(00)81717-1
[11] Fabian, C., Tilzer, L. and Sternson, L. (1981) Comparative binding affinities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen-receptors isolated from human-breast carcinoma—Correlation with blood- levels in patients with metastatic breast-cancer. Biopharmaceutics & Drug Disposition, 2, 381-390. doi:10.1002/bdd.2510020407
[12] Johnson, M.D., Zuo, H., Lee, K.H., Trebley, J.P., Rae, J.M., Weatherman, R.V., Desta, Z., Flockhart, D.A. and Skaar, T.C. (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Research and Treatment, 85, 151-159. doi:10.1023/B:BREA.0000025406.31193.e8
[13] Coezy, E., Borgna, J.L. and Rochefort, H. (1982) Tamoxifen and metabolites in Mcf7 cells—Correlation between binding to estrogen-receptor and inhibition of cell-growth. Cancer Research, 42, 317-323.
[14] Goetz, M.P., Rae, J.M., Suman, V.J., Safgren, S.L., Ames, M.M., Visscher, D.W., Reynolds, C., Couch, F.J., Lingle, W.L., Flockhart, D.A., Desta, Z., Perez, E.A. and Ingle, J.N. (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. Journal of Clinical Oncology, 23, 9312-9318. doi:10.1200/JCO.2005.03.3266
[15] Schroth, W., Antoniadou, L., Fritz, P., Schwab, M., Muerdter, T., Zanger, U.M., Simon, W., Eichelbaum, M. and Brauch, H. (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. Journal of Clinical Oncology, 25, 5187-5193. doi:10.1200/JCO.2007.12.2705
[16] Goetz, M.P., Knox, S.K., Suman, V.J., Rae, J.M., Safgren, S.L., Ames, M.M., Visscher, D.W., Reynolds, C., Couch, F.J., Lingle, W.L., Weinshilboum, R.M., Fritcher, E.G.B., Nibbe, A.M., Desta, Z., Nguyen, A., Flockhart, D.A., Perez, E.A. and Ingle, J.N. (2007) The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Research and Treatment, 101, 113-121. doi:10.1007/s10549-006-9428-0
[17] Kiyotani, K., Mushiroda, T., Sasa, M., Bando, Y., Sumitomo, I., Hosono, N., Kubo, M., Nakamura, Y. and Zembutsu, H. (2008) Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Science, 99, 995-999. doi:10.1111/j.1349-7006.2008.00780.x
[18] Xu, Y., Sun, Y., Yao, L., Shi, L., Wu, Y., Ouyang, T., Li, J., Wang, T., Fan, Z., Fan, T., Lin, B., He, L., Li, P. and Xie, Y. (2008) Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Annals of Oncology, 19, 1423-1429. doi:10.1093/annonc/mdn155
[19] Newman, W.G., Hadfield, K.D., Latif, A., Roberts, S.A., Shenton, A., McHague, C., Lalloo, F., Howell, S. and Evans, D.G. (2008) Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clinical Cancer Research, 14, 5913-5918. doi:10.1158/1078-0432.CCR-07-5235
[20] Nowell, S.A., Ahn, J.Y., Rae, J.M., Scheys, J.O., Trovato, A., Sweeney, C., MacLeod, S.L., Kadlubar, F.F. and Ambrosone, C.B. (2005) Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Research and Treatment, 91, 249-258. doi:10.1007/s10549-004-7751-x
[21] Okishiro, M., Taguchi, T., Kim, S.J., Shimazu, K., Tamaki, Y. and Noguchi, S. (2009) Polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer, 115, 952-961. doi:10.1002/cncr.24111
[22] Nowell, S., Sweeney, C., Winters, M., Stone, A., Lang, N. P., Hutchins, L.F., Kadlubar, F.F. and Ambrosone, C.B. (2002) Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. Journal of the National Cancer Institute, 94, 1635-1640.
[23] Wegman, P., Vainikka, L., Stal, O., Nordenskjold, B., Skoog, L., Rutqvist, L.E. and Wingren, S. (2005) Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Research, 7, R284-R290. doi:10.1186/bcr993
[24] Wegman, P., Elingarami, S., Carstensen, J., Stal, O., Nordenskjold, B. and Wingren, S. (2007) Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Research, 9, R7. doi:10.1186/bcr1640
[25] Osborne, C.K., Coronado, E., Allred, D.C., Wiebe, V. and Degregorio, M. (1991) Acquired tamoxifen resistance—Correlation with reduced breast-tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. Journal of the National Cancer Institute, 83, 1477-1482. doi:10.1093/jnci/83.20.1477
[26] Osborne, C.K., Wiebe, V.J., Mcguire, WL., Ciocca, D.R. and Degregorio, M.W. (1992) Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast-cancer patients. Journal of Clinical Oncology, 10, 304-310.
[27] Hermkens, P.H., Kamp, S., Lusher, S. and Veeneman, G.H. (2006) Non-steroidal steroid receptor modulators. IDrugs, 9, 488-494.
[28] Grese, T.A., Sluka, J.P., Bryant, H.U., Cullinan, G.J., Glasebrook, A.L., Jones, C.D., Matsumoto, K., Palkowitz, A.D., Sato, M., Termine, J.D., Winter, M.A., Yang, N.N. and Dodge, J.A. (1997) Molecular determinants of tissue selectivity in estrogen receptor modulators. Proceedings of the National Academy of Sciences of the United States of America, 94, 14105-14110. doi:10.1073/pnas.94.25.14105
[29] Liu, H., Park, W.C., Bentrem, D.J., McKian, K.P., De los Reyes, A., Loweth, J.A., Schafer, J.M., Zapf, J.W. and Jordan, V.C. (2002) Structure-function relationships of the raloxifene-estrogen receptor-alpha complex for regulating transforming growth factor-alpha expression in breast cancer cells. Journal of Biological Chemistry, 277, 9189-9198. doi:10.1074/jbc.M108335200
[30] DeMichele, A., Troxel, A.B., Berlin, J. A., Weber, A.L., Bunin, G.R., Turzo, E., Schinnar, R., Burgh, D., Berlin, M., Rubin, S.C., Rebbeck, T.R. and Strom, B.L. (2008) Impact of raloxifene or tamoxifen use on endometrial cancer risk: A population-based case-control study. Journal of Clinical Oncology, 26, 4151-4159. doi:10.1200/JCO.2007.14.0921
[31] Brzozowski, A.M., Pike, A.C., Dauter, Z., Hubbard, R.E., Bonn, T., Engstrom, O., Ohman, L., Greene, G.L., Gustafsson, J.A. and Carlquist, M. (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature, 389, 753-758. doi:10.1038/39645
[32] Heldring, N., Pawson, T., McDonnell, D., Treuter, E., Gustafsson, J.A. and Pike, A.C. (2007) Structural insights into corepressor recognition by antagonist-bound estrogen receptors. Jounal of Biological Chemistry, 282, 10449-10455. doi:10.1074/jbc.M611424200
[33] Kong, E.H., Heldring, N., Gustafsson, J.A., Treuter, E., Hubbard, R.E. and Pike, A.C. (2005) Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor. Proceedings of the National Academy of Sciences of the United States of America, 102, 3593-3598. doi:10.1073/pnas.0407189102
[34] Blizzard, T.A., DiNinno, F., Morgan, J.D., Chen, H.Y., Wu, J.Y., Kim, S., Chan, W., Birzin, E.T., Yang, Y.T., Pai, L.Y., Fitzgerald, P.M.D., Sharma, N., Li, Y., Zhang, Z.P., Hayes, E.C., DaSilva, C.A., Tang, W., Rohrer, S.P., Schaeffer, J.M. and Hammond, M.L. (2005) Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers. Bioorganic & Medicinal Chemistry Letters, 15, 107-113. doi:10.1016/j.bmcl.2004.10.036
[35] Molecular Operating Enviroment (2010). Chemical Computing Group, Montreal, Canada.
[36] Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W. and Klein, M.L. (1983) Comparison of simple potential functions for simulating liquid water. Journal of Chemical Physics, 79, 926-935. doi:10.1063/1.445869
[37] Krieger, E., Darden, T., Nabuurs, S.B., Finkelstein, A. and Vriend, G. (2004) Making optimal use of empirical energy functions: Force-field parameterization in crystal space. Proteins-Structure Function and Bioinformatics, 57, 678-683. doi:10.1002/prot.20251
[38] Duan, Y., Wu, C., Chowdhury, S., Lee, M.C., Xiong, G., Zhang, W., Yang, R., Cieplak, P., Luo, R., Lee, T., Caldwell, J., Wang, J. and Kollman, P. (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. Journal of Computational Chemistry, 24, 1999-2012. doi:10.1002/jcc.10349
[39] Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A. and Case, D.A. (2004) Development and testing of a general amber force field. Journal of Computational Chemistry, 25, 1157-1174. doi:10.1002/jcc.20035
[40] Jakalian, A., Jack, D.B. and Bayly, C.I. (2002) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. Journal of Computational Chemistry, 23, 1623-1641. doi:10.1002/jcc.10128
[41] Krieger, E., Nielsen, J.E., Spronk, C.A. and Vriend, G. (2006) Fast empirical pKa prediction by Ewald summation. Jounal of Molecular Graphics & Modelling, 25, 481-486. doi:10.1016/j.jmgm.2006.02.009
[42] Blizzard, T.A., Morgan, J.D., Chan, W.D., Birzin, E.T., Pai, L.Y., Hayes, E.C., DaSilva, C.A., Mosley, R.T., Yang, Y.T., Rohrer, S.P., DiNinno, F. and Hammond, M.L. (2005) Estrogen receptor ligands. Part 14: Application of novel antagonist side chains to existing platforms. Bioorganic & Medicinal Chemistry Letters, 15, 5124-5128. doi:10.1016/j.bmcl.2005.08.084
[43] Blizzard, T.A., DiNinno, F., Chen, H.Y., Kim, S., Wu, J.Y., Chan, W.D., Birzin, E.T., Yang, Y.T., Pal, L.Y., Hayes, E.C., DaSilva, C.A., Rohrer, S.P., Schaeffer, J.M. and Hammond, M.L. (2005) Estrogen receptor ligands. Part 13: Dihydrobenzoxathiin SERAMs with an optimized antagonist side chain. Bioorganic & Medicinal Chemistry Letters, 15, 3912-3916. doi:10.1016/j.bmcl.2005.05.089
[44] Tan, Q., Blizzard, T.A., Morgan, J.D., Birzin, E.T., Chan, W.D., Yang, Y.T., Pai, L.Y., Hayes, E.C., DaSilva, C.A., Warrier, S., Yudkovitz, J., Wilkinson, H.A., Sharma, N., Fitzgerald, P.M.D., Li, S., Colwell, L., Fisher, J.E., Adamski, S., Reszka, A.A., Kimmel, D., DiNinno, F., Rohrer, S.P., Freedman, L.P., Schaeffer, J.M. and Hammond, M.L. (2005) Estrogen receptor ligands. Part 10: Chromanes: Old scaffolds for new SERAMs. Bioorganic & Medicinal Chemistry Letters, 15, 1675-1681. doi:10.1016/j.bmcl.2005
[45] Liu, J., Birzin, E.T., Chan, W.D., Yang, Y.T., Pai, L.Y., DaSilva, C., Hayes, E.C., Mosley, R.T., DiNinno, F., Rohrer, S.P., Schaeffer, J.M. and Hammond, M.L. (2005) Estrogen receptor ligands. Part 11: Synthesis and activity of isochromans and isothiochromans. Bioorganic & Medicinal Chemistry Letters, 15, 715-718. doi:10.1016/j.bmcl.2004.11.018
[46] Blizzard, T.A., DiNinno, F., Morgan, J.D., Chen, H.Y., Wu, J.Y., Gude, C., Kim, S., Chan, W.D., Birzin, E.T., Yang, Y.T., Pai, L.Y., Zhang, Z.P., Hayes, E.C., DaSilva, C.A., Tang, W., Rohrer, S.P., Schaeffer, J.M. and Hammond, M.L. (2004) Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains. Bioorganic & Medicinal Chemistry Letters, 14, 3861-3864. doi:10.1016/j.bmcl.2004.05.074
[47] Blizzard, T.A., DiNinno, F., Morgan, J.D., Wu, J.Y., Chen, H.Y., Kim, S., Chan, W.D., Birzin, E.T., Yang, Y.T., Pai, L.Y., Zhang, Z.P., Hayes, E.C., DaSilva, C.A., Tang, W., Rohrer, S.P., Schaeffer, J.M. and Hammond, M.L. (2004) Estrogen receptor ligands. Part 8: Dihydrobenzoxathiin SERAMs with heteroatom-substituted side chains. Bioorganic & Medicinal Chemistry Letters, 14, 3865-3868. doi:10.1016/j.bmcl.2004.05.073
[48] Tan, Q., Birzin, E.T., Chan, W., Yang, Y.T., Pai, L.Y., Hayes, E.C., DaSilva, C.A., DiNinno, F., Rohrer, S.P., Schaeffer, J.M. and Hammond, M.L. (2004) Estrogen receptor ligands. Part 5: The SAR of dihydrobenzoxathiins containing modified basic side chains. Bioorganic & Medicinal Chemistry Letters, 14, 3747-3751. doi:10.1016/j.bmcl.2004.04.100
[49] Dayan, G., Lupien, M., Auger, A., Anghel, S.I., Rocha, W., Croisetiere, S., Katzenellenbogen, J.A. and Mader, S. (2006) Tamoxifen and raloxifene differ in their functional interactions with aspartate 351 of estrogen receptor alpha. Molecular Pharmacology, 70, 579-588. doi:10.1124/mol.105.021931
[50] MacGregor Schafer, J., Liu, H., Bentrem, D.J., Zapf, J.W. and Jordan, V.C. (2000) Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 351. Cancer Research, 60, 5097-5105
[51] Anghel, S.I., Perly, V., Melancon, G., Barsalou, A., Chagnon, S., Rosenauer, A., Miller, W.H. Jr. and Mader, S. (2000) Aspartate 351 of estrogen receptor alpha is not crucial for the antagonist activity of antiestrogens. Jounal of Biological Chememistry, 275, 20867-20872. doi:10.1074/jbc.M002098200

  
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