| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Department of Pharmacology and Cancer Biology (A.L.W., S.C.N., J.D.N., D.P.M.), Duke University Medical Center, Durham, North Carolina 27710; and Novalon Pharmaceutical Corporation (L.A.P., D.J.C., D.M.F.), Durham, North Carolina 27703
Address all correspondence and requests for reprints to: Donald P. McDonnell, Department of Pharmacology and Cancer Biology, Box 3813 Duke University Medical Center, Durham, North Carolina 27710. E-mail: mcdon016{at}acpub.duke.edu
Antiestrogens such as tamoxifen are one of the most effective methods
of treating estrogen receptor (ER
) positive breast cancers; however,
the effectiveness of this therapy is limited by the almost universal
development of resistance to the drug. If antiestrogens are recognized
differently by the cell as it has been suggested, then in disease
conditions where tamoxifen fails to function effectively, a
mechanistically different antiestrogen might yield successful results.
Although many antiestrogens have been developed, a direct comparison of
their mechanisms of action is lacking, thus limiting their utility.
Therefore, to determine if there are mechanistic differences among
available antiestrogens, we have carried out a comprehensive analysis
of the molecular mechanisms of action of 4-hydroxy-tamoxifen (4OHT),
idoxifene, raloxifene, GW7604, and ICI 182,780. Using a novel set of
peptides that recognize different surfaces on ER, we have found that
following binding to ER, each ligand induces a distinct ER-ligand
conformation. Furthermore, transcriptional assays indicate that each
ER-ligand complex is recognized distinctly by the transcription
machinery, and consequently, antiestrogens vary in their ability to
inhibit estradiol- and 4OHT-mediated activities. Relative binding
assays have shown that the affinity of these ligands for ER is not
always representative of their inhibitory activity. Using this assay,
we have also shown that the pharmacology of each antiestrogen is
influenced differently by hormone binding proteins. Furthermore,
GW7604, like ICI 182,780, but unlike the other antiestrogens evaluated,
decreases the stability of the receptor. Overall, our results indicate
that there are clear mechanistic distinctions among each of the
antiestrogens studied. However, GW7604 and ICI 182,780 differ more
significantly from tamoxifen than idoxifene and raloxifene. These data,
which reveal differences among antiestrogens, should assist in the
selection of compounds for the clinical regulation of ER function.
This article has been cited by other articles:
 |
|
 |
|
  N. B. Berry, M. Fan, and K. P. Nephew Estrogen Receptor-{alpha} Hinge-Region Lysines 302 and 303 Regulate Receptor Degradation by the Proteasome Mol. Endocrinol., July 1, 2008; 22(7): 1535 - 1551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lupien, M. Jeyakumar, E. Hebert, K. Hilmi, D. Cotnoir-White, C. Loch, A. Auger, G. Dayan, G.-A. Pinard, J.-M. Wurtz, et al. Raloxifene and ICI182,780 Increase Estrogen Receptor-{alpha} Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12 Mol. Endocrinol., April 1, 2007; 21(4): 797 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Howell Pure oestrogen antagonists for the treatment of advanced breast cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 689 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Dayan, M. Lupien, A. Auger, S. I. Anghel, W. Rocha, S. Croisetiere, J. A. Katzenellenbogen, and S. Mader Tamoxifen and Raloxifene Differ in Their Functional Interactions with Aspartate 351 of Estrogen Receptor {alpha} Mol. Pharmacol., August 1, 2006; 70(2): 579 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. I. Moreira, J. Custodio, A. Moreno, C. R. Oliveira, and M. S. Santos Tamoxifen and Estradiol Interact with the Flavin Mononucleotide Site of Complex I Leading to Mitochondrial Failure J. Biol. Chem., April 14, 2006; 281(15): 10143 - 10152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Long and K. P. Nephew Fulvestrant (ICI 182,780)-dependent Interacting Proteins Mediate Immobilization and Degradation of Estrogen Receptor-{alpha} J. Biol. Chem., April 7, 2006; 281(14): 9607 - 9615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lipfert, J. E. Fisher, N. Wei, A. Scafonas, Q. Su, J. Yudkovitz, F. Chen, S. Warrier, E. T. Birzin, S. Kim, et al. Antagonist-Induced, Activation Function-2-Independent Estrogen Receptor {alpha} Phosphorylation Mol. Endocrinol., March 1, 2006; 20(3): 516 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Hall and D. P. McDonnell Coregulators in Nuclear Estrogen Receptor Action: From Concept to Therapeutic Targeting Mol. Interv., December 1, 2005; 5(6): 343 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fan, A. Park, and K. P. Nephew CHIP (Carboxyl Terminus of Hsc70-Interacting Protein) Promotes Basal and Geldanamycin-Induced Degradation of Estrogen Receptor-{alpha} Mol. Endocrinol., December 1, 2005; 19(12): 2901 - 2914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Larson, D. L. Osburn, K. Schmitz, L. Giampa, S.-M. Mong, K. Marschke, H. M. Seidel, J. Rosen, and A. Negro-Vilar Peptide Binding Identifies an ER{alpha} Conformation That Generates Selective Activity in Multiple In Vitro Assays J Biomol Screen, September 1, 2005; 10(6): 590 - 598. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Callige, I. Kieffer, and H. Richard-Foy CSN5/Jab1 Is Involved in Ligand-Dependent Degradation of Estrogen Receptor {alpha} by the Proteasome Mol. Cell. Biol., June 1, 2005; 25(11): 4349 - 4358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Wright, R. L. Stouffer, and K. D. Rodland High-Dose Estrogen and Clinical Selective Estrogen Receptor Modulators Induce Growth Arrest, p21, and p53 in Primate Ovarian Surface Epithelial Cells J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3688 - 3695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. McDonnell The Molecular Pharmacology of Estrogen Receptor Modulators: Implications for the Treatment of Breast Cancer Clin. Cancer Res., January 15, 2005; 11(2): 871s - 877s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Wu, R. Burghardt, and S. Safe Vitamin D-interacting Protein 205 (DRIP205) Coactivation of Estrogen Receptor {alpha} (ER{alpha}) Involves Multiple Domains of Both Proteins J. Biol. Chem., December 17, 2004; 279(51): 53602 - 53612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Shao, E. K. Keeton, D. P. McDonnell, and M. Brown Coactivator AIB1 links estrogen receptor transcriptional activity and stability PNAS, August 10, 2004; 101(32): 11599 - 11604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Pinzone, H. Stevenson, J. S. Strobl, and P. E. Berg Molecular and Cellular Determinants of Estrogen Receptor {alpha} Expression Mol. Cell. Biol., June 1, 2004; 24(11): 4605 - 4612. [Full Text] [PDF]
|
|
|
|
|
|
D. M. Lonard, S. Y. Tsai, and B. W. O'Malley Selective Estrogen Receptor Modulators 4-Hydroxytamoxifen and Raloxifene Impact the Stability and Function of SRC-1 and SRC-3 Coactivator Proteins Mol. Cell. Biol., January 1, 2004; 24(1): 14 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Bentrem, J. E. Fox, S. T. Pearce, H. Liu, S. Pappas, D. Kupfer, J. W. Zapf, and V. C. Jordan Distinct Molecular Conformations of the Estrogen Receptor {alpha} Complex Exploited by Environmental Estrogens Cancer Res., November 1, 2003; 63(21): 7490 - 7496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wormke, M. Stoner, B. Saville, K. Walker, M. Abdelrahim, R. Burghardt, and S. Safe The Aryl Hydrocarbon Receptor Mediates Degradation of Estrogen Receptor {alpha} through Activation of Proteasomes Mol. Cell. Biol., March 15, 2003; 23(6): 1843 - 1855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Webb, P. Nguyen, and P. J. Kushner Differential SERM Effects on Corepressor Binding Dictate ERalpha Activity in Vivo J. Biol. Chem., February 21, 2003; 278(9): 6912 - 6920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Obrero, D. V. Yu, and D. J. Shapiro Estrogen Receptor-dependent and Estrogen Receptor-independent Pathways for Tamoxifen and 4-Hydroxytamoxifen-induced Programmed Cell Death J. Biol. Chem., November 15, 2002; 277(47): 45695 - 45703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Hall and K. S. Korach Analysis of the Molecular Mechanisms of Human Estrogen Receptors alpha and beta Reveals Differential Specificity in Target Promoter Regulation by Xenoestrogens J. Biol. Chem., November 8, 2002; 277(46): 44455 - 44461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Huang, J. D. Norris, and D. P. McDonnell Identification of a Negative Regulatory Surface within Estrogen Receptor {alpha} Provides Evidence in Support of a Role for Corepressors in Regulating Cellular Responses to Agonists and Antagonists Mol. Endocrinol., August 1, 2002; 16(8): 1778 - 1792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Dardes, R. M. O'Regan, C. Gajdos, S. P. Robinson, D. Bentrem, A. De Los Reyes, and V. C. Jordan Effects of a New Clinically Relevant Antiestrogen (GW5638) Related to Tamoxifen on Breast and Endometrial Cancer Growth in Vivo Clin. Cancer Res., June 1, 2002; 8(6): 1995 - 2001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Peleg, M. Uskokovic, A. Ahene, B. Vickery, and Z. Avnur Cellular and Molecular Events Associated with the Bone-Protecting Activity of the Noncalcemic Vitamin D Analog Ro-26-9228 in Osteopenic Rats Endocrinology, May 1, 2002; 143(5): 1625 - 1636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Simoncini, A. R. Genazzani, and J. K. Liao Nongenomic Mechanisms of Endothelial Nitric Oxide Synthase Activation by the Selective Estrogen Receptor Modulator Raloxifene Circulation, March 19, 2002; 105(11): 1368 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Hall, D. P. McDonnell, and K. S. Korach Allosteric Regulation of Estrogen Receptor Structure, Function, and Coactivator Recruitment by Different Estrogen Response Elements Mol. Endocrinol., March 1, 2002; 16(3): 469 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Brady, S. Desai, L. M. Gayo-Fung, S. Khammungkhune, J. A. McKie, E. O'Leary, L. Pascasio, M. K. Sutherland, D. W. Anderson, S. S. Bhagwat, et al. Effects of SP500263, a Novel, Potent Antiestrogen, on Breast Cancer Cells and in Xenograft Models Cancer Res., March 1, 2002; 62(5): 1439 - 1442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. McDonnell, C. E. Connor, A. Wijayaratne, C.-y. Chang, and J. D. Norris Definition of the Molecular and Cellular Mechanisms Underlying the Tissue-selective Agonist/Antagonist Activities of Selective Estrogen Receptor Modulators Recent Prog. Horm. Res., January 1, 2002; 57(1): 295 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Jordan, S. Gapstur, and M. Morrow Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease J Natl Cancer Inst, October 3, 2001; 93(19): 1449 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Greenberger, T. Annable, K. I. Collins, B. S. Komm, C. R. Lyttle, C. P. Miller, P. G. Satyaswaroop, Y. Zhang, and P. Frost A New Antiestrogen, 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride (ERA-923), Inhibits the Growth of Tamoxifen-sensitive and -resistant Tumors and Is Devoid of Uterotropic Effects in Mice and Rats Clin. Cancer Res., October 1, 2001; 7(10): 3166 - 3177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Jordan Selective Estrogen Receptor Modulation: A Personal Perspective Cancer Res., August 1, 2001; 61(15): 5683 - 5687. [Full Text] [PDF]
|
|
|
|
|
|
J. M. Schafer, E.-S. Lee, R. C. Dardes, D. Bentrem, R. M. O'Regan, A. De Los Reyes, and V. C. Jordan Analysis of Cross-Resistance of the Selective Estrogen Receptor Modulators Arzoxifene (LY353381) and LY117018 in Tamoxifen-stimulated Breast Cancer Xenografts Clin. Cancer Res., August 1, 2001; 7(8): 2505 - 2512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bagatell, O. Khan, G. Paine-Murrieta, C. W. Taylor, S. Akinaga, and L. Whitesell Destabilization of Steroid Receptors by Heat Shock Protein 90-binding Drugs: A Ligand-independent Approach to Hormonal Therapy of Breast Cancer Clin. Cancer Res., July 1, 2001; 7(7): 2076 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Connor, J. D. Norris, G. Broadwater, T. M. Willson, M. M. Gottardis, M. W. Dewhirst, and D. P. McDonnell Circumventing Tamoxifen Resistance in Breast Cancers Using Antiestrogens That Induce Unique Conformational Changes in the Estrogen Receptor Cancer Res., April 1, 2001; 61(7): 2917 - 2922. [Abstract] [Full Text]
|
|
|
|
|
|
D. J. Bentrem, R. C. Dardes, H. Liu, J. MacGregor-Schafer, J. W. Zapf, and V. C. Jordan Molecular Mechanism of Action at Estrogen Receptor {{alpha}} of a New Clinically Relevant Antiestrogen (GW7604) Related to Tamoxifen Endocrinology, February 1, 2001; 142(2): 838 - 846. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Rossberg, S. J. Murphy, R. J. Traystman, P. D. Hurn, and H. A. Kontos LY353381.HCl, a Selective Estrogen Receptor Modulator, and Experimental Stroke Editorial Comment Stroke, December 1, 2000; 31(12): 3041 - 3046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Schafer, E. S. Lee, R. M. O'Regan, K. Yao, and V. C. Jordan Rapid Development of Tamoxifen-stimulated Mutant p53 Breast Tumors (T47D) in Athymic Mice Clin. Cancer Res., November 1, 2000; 6(11): 4373 - 4380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Bowers, V. V. Tyulmenkov, S. C. Jernigan, and C. M. Klinge Resveratrol Acts as a Mixed Agonist/Antagonist for Estrogen Receptors {alpha} and {beta} Endocrinology, October 1, 2000; 141(10): 3657 - 3667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tcherepanova, P. Puigserver, J. D. Norris, B. M. Spiegelman, and D. P. McDonnell Modulation of Estrogen Receptor-alpha Transcriptional Activity by the Coactivator PGC-1 J. Biol. Chem., May 19, 2000; 275(21): 16302 - 16308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Wijayaratne and D. P. McDonnell The Human Estrogen Receptor-alpha Is a Ubiquitinated Protein Whose Stability Is Affected Differentially by Agonists, Antagonists, and Selective Estrogen Receptor Modulators J. Biol. Chem., September 14, 2001; 276(38): 35684 - 35692. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
