This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pink, J. J. Articles by Jordan, V. C. Search for Related Content PubMed PubMed Citation Articles by Pink, J. J. Articles by Jordan, V. C.

Models of Estrogen Receptor Regulation by Estrogens and Antiestrogens in Breast Cancer Cell Lines¹

Department of Human Oncology, University of Wisconisn Comprehensive Cancer Center, Madison, Wisconsin 53792 [J. J. P., V. C. J.], and Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611 [V. C. J.]

The expression and stability of the estrogen receptor (ER) is the result of a complex process that is modulated by estrogens and antiestrogens. Regulation of the steady-state ER mRNA and protein levels in breast cancer cells appears to be the result of either of two distinct regulatory mechanisms. Estrogen exposure causes a rapid down-regulation of the steady-state level of ER mRNA and protein in model I regulation, as exemplified by the MCF-7:WS8 cell line. Conversely, in model II regulation, as observed in the T47D:A18 cell line, estrogen exposure causes an increase in the steady-state ER mRNA level and a maintenance of the ER protein level. In both these cell lines, the nonsteroidal antiestrogen 4-hydroxytamoxifen has little effect on the mRNA level but causes a net accumulation of the ER protein over time. In contrast, the pure antiestrogen ICI 182,780 causes a dramatic reduction of the ER protein in both the MCF-7:WS8 and T47D:A18 cell lines. This loss has little effect upon the ER mRNA level in the MCF-7:WS8 cells but leads to a decline in the ER mRNA in the T47D:A18 cells. The estrogen-independent MCF-7:2A cell line, which has adapted to growth in estrogen free media, expresses two forms of the ER, a wild-type M_r66,000 ER and a mutant M_r77,000 ER (ER⁷⁷). ER⁷⁷ is the product of a genomic rearrangement resulting in a tandem duplication of exons 6 and 7 (J. J. Pink et al., Nucleic Acids Res., 24: 962–969, 1996). This exon duplication has abolished ligand binding by this protein. Here we demonstrate that the loss of ligand binding has eliminated the effects of 4-OHT and ICI 182,780 on the steady-state ER⁷⁷ protein level. However, in the MCF-7:2A cells, antiestrogens affect the wild-type ER protein in the same manner as observed in the MCF-7:WS8 and T47D:A18 cells. Estrogen regulates the ER mRNA and wild-type ER and ER⁷⁷ proteins in the MCF-7:2A cells in the same manner as observed in the MCF-7:WS8 cells. Interestingly, treatment of the MCF-7:2A cells with ICI 182,780 causes a slight increase in ER mRNA, which is reflected in a net increase in the ER⁷⁷ protein but a dramatic decrease in the wild-type ER. The models presented here describe the response of two human breast cancer cell lines in short-term studies. These distinct regulation pathways are predictive of the response of these cell lines to long-term estrogen deprivation. This study illustrates two alternative regulation pathways that are present in ER-positive, estrogen-dependent breast cancer cells. This variable response highlights the diversity of responses potentially present in the heterogeneous cell populations of clinically observed breast cancer.

¹ This work was supported by NIH Grant CA 32713 to V.C.J. and in part by a fellowship to J. J. P. from the Department of Human Oncology, NIH Training Grant 5T32-CA09471.

² To whom requests for reprints should be addressed, at Robert H. Lurie Cancer Center, Northwestern University Medical School, 303 East Chicago Avenue, Olsen Pavilion 8258, Chicago, IL 60611.

Received 12/ 8/95. Accepted 3/18/96.

This article has been cited by other articles:

				C. C Valley, N. M Solodin, G. L Powers, S. J Ellison, and E. T Alarid Temporal variation in estrogen receptor-{alpha} protein turnover in the presence of estrogen J. Mol. Endocrinol., January 1, 2008; 40(1): 23 - 34. [Abstract] [Full Text] [PDF]

				V. C. Jordan Estrogen Receptors in BRCA1-Mutant Breast Cancer: Now You See Them, Now You Don't J Natl Cancer Inst, November 21, 2007; 99(22): 1655 - 1657. [Full Text] [PDF]

				P. A. Pioli, A. L. Jensen, L. K. Weaver, E. Amiel, Z. Shen, L. Shen, C. R. Wira, and P. M. Guyre Estradiol Attenuates Lipopolysaccharide-Induced CXC Chemokine Ligand 8 Production by Human Peripheral Blood Monocytes J. Immunol., November 1, 2007; 179(9): 6284 - 6290. [Abstract] [Full Text] [PDF]

				E. A. Ariazi, A. Leitao, T. I. Oprea, B. Chen, T. Louis, A. M. Bertucci, C. G.N. Sharma, S. D. Gill, H. R. Kim, H. A. Shupp, et al. Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen Mol. Cancer Ther., November 1, 2007; 6(11): 2817 - 2827. [Abstract] [Full Text] [PDF]

				J. Grisouard, S. Medunjanin, A. Hermani, A. Shukla, and D. Mayer Glycogen Synthase Kinase-3 Protects Estrogen Receptor {alpha} from Proteasomal Degradation and Is Required for Full Transcriptional Activity of the Receptor Mol. Endocrinol., October 1, 2007; 21(10): 2427 - 2439. [Abstract] [Full Text] [PDF]

				J. Chen, K. A. Power, J. Mann, A. Cheng, and L. U. Thompson Flaxseed Alone or in Combination with Tamoxifen Inhibits MCF-7 Breast Tumor Growth in Ovariectomized Athymic Mice with High Circulating Levels of Estrogen Experimental Biology and Medicine, September 1, 2007; 232(8): 1071 - 1080. [Abstract] [Full Text] [PDF]

				E. T. Alarid Lives and Times of Nuclear Receptors Mol. Endocrinol., September 1, 2006; 20(9): 1972 - 1981. [Abstract] [Full Text] [PDF]

				X. Lin, Y. Yu, H. Zhao, Y. Zhang, J. Manela, and D. A. Tonetti Overexpression of PKC{alpha} is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model Carcinogenesis, August 1, 2006; 27(8): 1538 - 1546. [Abstract] [Full Text] [PDF]

				C. Delfour, P. Roger, C. Bret, M.-L. Berthe, P. Rochaix, N. Kalfa, P. Raynaud, F. Bibeau, T. Maudelonde, and N. Boulle RCL2, a New Fixative, Preserves Morphology and Nucleic Acid Integrity in Paraffin-Embedded Breast Carcinoma and Microdissected Breast Tumor Cells J. Mol. Diagn., May 1, 2006; 8(2): 157 - 169. [Abstract] [Full Text] [PDF]

				H.-P. Yu, M. A. Choudhry, T. Shimizu, Y.-C. Hsieh, M. G. Schwacha, S. Yang, and I. H. Chaudry Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-{beta}-dependent HO-1 J. Leukoc. Biol., February 1, 2006; 79(2): 277 - 284. [Abstract] [Full Text] [PDF]

				A. S. Levenson, K. E. Thurn, L. A. Simons, D. Veliceasa, J. Jarrett, C. Osipo, V. C. Jordan, O. V. Volpert, R. L. Satcher Jr., and R. B. Gartenhaus MCT-1 Oncogene Contributes to Increased In vivo Tumorigenicity of MCF7 Cells by Promotion of Angiogenesis and Inhibition of Apoptosis Cancer Res., December 1, 2005; 65(23): 10651 - 10656. [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]

				R I Nicholson, C Staka, F Boyns, I R Hutcheson, and J M W Gee Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy Endocr. Relat. Cancer, December 1, 2004; 11(4): 623 - 641. [Abstract] [Full Text] [PDF]

				M. H. Herynk and S. A. W. Fuqua Estrogen Receptor Mutations in Human Disease Endocr. Rev., December 1, 2004; 25(6): 869 - 898. [Abstract] [Full Text] [PDF]

				M. Fan, H. Nakshatri, and K. P. Nephew Inhibiting Proteasomal Proteolysis Sustains Estrogen Receptor-{alpha} Activation Mol. Endocrinol., November 1, 2004; 18(11): 2603 - 2615. [Abstract] [Full Text] [PDF]

				N Angelopoulos, V Barbounis, S Livadas, D Kaltsas, and G Tolis Effects of estrogen deprivation due to breast cancer treatment Endocr. Relat. Cancer, September 1, 2004; 11(3): 523 - 535. [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.-x. Zhang, D. C. Labaree, G. Mor, and R. B. Hochberg Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3527 - 3535. [Abstract] [Full Text] [PDF]

				D. C. Spink, B. H. Katz, M. M. Hussain, B. T. Pentecost, Z. Cao, and B. C. Spink Estrogen regulates Ah responsiveness in MCF-7 breast cancer cells Carcinogenesis, December 1, 2003; 24(12): 1941 - 1950. [Abstract] [Full Text] [PDF]

				H. Liu, E.-S. Lee, C. Gajdos, S. T. Pearce, B. Chen, C. Osipo, J. Loweth, K. McKian, A. De Los Reyes, L. Wing, et al. Apoptotic Action of 17{beta}-Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo J Natl Cancer Inst, November 5, 2003; 95(21): 1586 - 1597. [Abstract] [Full Text] [PDF]

				J. Lu, A. Pierron, and K. Ravid An Adenosine Analogue, IB-MECA, Down-Regulates Estrogen Receptor {alpha} and Suppresses Human Breast Cancer Cell Proliferation Cancer Res., October 1, 2003; 63(19): 6413 - 6423. [Abstract] [Full Text] [PDF]

				E. T. Alarid, M. T. Preisler-Mashek, and N. M. Solodin Thyroid Hormone Is an Inhibitor of Estrogen-Induced Degradation of Estrogen Receptor-{alpha} Protein: Estrogen-Dependent Proteolysis Is Not Essential for Receptor Transactivation Function in the Pituitary Endocrinology, August 1, 2003; 144(8): 3469 - 3476. [Abstract] [Full Text] [PDF]

				J. Faridi, L. Wang, G. Endemann, and R. A. Roth Expression of Constitutively Active Akt-3 in MCF-7 Breast Cancer Cells Reverses the Estrogen and Tamoxifen Responsivity of these Cells in Vivo Clin. Cancer Res., August 1, 2003; 9(8): 2933 - 2939. [Abstract] [Full Text] [PDF]

				K. M. M. Kelley, B. G. Rowan, and M. Ratnam Modulation of the Folate Receptor {alpha} Gene by the Estrogen Receptor: Mechanism and Implications in Tumor Targeting Cancer Res., June 1, 2003; 63(11): 2820 - 2828. [Abstract] [Full Text] [PDF]

				M. Fan, R. M. Bigsby, and K. P. Nephew The NEDD8 Pathway Is Required for Proteasome-Mediated Degradation of Human Estrogen Receptor (ER)-{alpha} and Essential for the Antiproliferative Activity of ICI 182,780 in ER{alpha}-Positive Breast Cancer Cells Mol. Endocrinol., March 1, 2003; 17(3): 356 - 365. [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]

				M. Fan, X. Long, J. A. Bailey, C. A. Reed, E. Osborne, E. A. Gize, E. A. Kirk, R. M. Bigsby, and K. P. Nephew The Activating Enzyme of NEDD8 Inhibits Steroid Receptor Function Mol. Endocrinol., February 1, 2002; 16(2): 315 - 330. [Abstract] [Full Text] [PDF]

				R. C. Dardes, D. Bentrem, R. M. O'Regan, J. M. Schafer, and V. C. Jordan Effects of the New Selective Estrogen Receptor Modulator LY353381.HCl (Arzoxifene) on Human Endometrial Cancer Growth in Athymic Mice Clin. Cancer Res., December 1, 2001; 7(12): 4149 - 4155. [Abstract] [Full Text] [PDF]

				M. J. Chisamore, Y. Ahmed, D. J. Bentrem, V. C. Jordan, and D. A. Tonetti Novel Antitumor Effect of Estradiol in Athymic Mice Injected with a T47D Breast Cancer Cell Line Overexpressing Protein Kinase C{alpha} Clin. Cancer Res., October 1, 2001; 7(10): 3156 - 3165. [Abstract] [Full Text] [PDF]

				J. F. Robertson, R. I. Nicholson, N. J. Bundred, E. Anderson, Z. Rayter, M. Dowsett, J. N. Fox, J. M. W. Gee, A. Webster, A. E. Wakeling, et al. Comparison of the Short-Term Biological Effects of 7{alpha}-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17{beta}-diol (Faslodex) versus Tamoxifen in Postmenopausal Women with Primary Breast Cancer Cancer Res., September 1, 2001; 61(18): 6739 - 6746. [Abstract] [Full Text] [PDF]

				M. J. E. Mourits, E. G. E. De Vries, P. H. B. Willemse, K. A. Ten Hoor, H. Hollema, and A. G. J. Van der Zee TAMOXIFEN TREATMENT AND GYNECOLOGIC SIDE EFFECTS: A REVIEW Obstet. Gynecol., May 1, 2001; 97(5): 855 - 866. [Abstract] [Full Text] [PDF]

				A. McDougal, M. Wormke, J. Calvin, and S. Safe Tamoxifen-induced Antitumorigenic/Antiestrogenic Action Synergized by a Selective Aryl Hydrocarbon Receptor Modulator Cancer Res., May 1, 2001; 61(10): 3902 - 3907. [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]

				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]

				N. Platet, S. Cunat, D. Chalbos, H. Rochefort, and M. Garcia Unliganded and Liganded Estrogen Receptors Protect against Cancer Invasion via Different Mechanisms Mol. Endocrinol., July 1, 2000; 14(7): 999 - 1009. [Abstract] [Full Text]

				S. Masuda, T. Kobayashi, M. Chikuma, M. Nagao, and R. Sasaki The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1038 - E1044. [Abstract] [Full Text] [PDF]

				E. T. Alarid, N. Bakopoulos, and N. Solodin Proteasome-Mediated Proteolysis of Estrogen Receptor: A Novel Component in Autologous Down-Regulation Mol. Endocrinol., September 1, 1999; 13(9): 1522 - 1534. [Abstract] [Full Text]

				J. I. MacGregor Schafer, H. Liu, D. A. Tonetti, and V. C. Jordan The Interaction of Raloxifene and the Active Metabolite of the Antiestrogen EM-800 (SC 5705) with the Human Estrogen Receptor Cancer Res., September 1, 1999; 59(17): 4308 - 4313. [Abstract] [Full Text] [PDF]

				M. S. Ricci, D. G. Toscano, C. J. Mattingly, and W. A. Toscano Jr. Estrogen Receptor Reduces CYP1A1 Induction in Cultured Human Endometrial Cells J. Biol. Chem., February 5, 1999; 274(6): 3430 - 3438. [Abstract] [Full Text] [PDF]

				J. Devin-Leclerc, X. Meng, F. Delahaye, P. Leclerc, E.-E. Baulieu, and M.-G. Catelli Interaction and Dissociation by Ligands of Estrogen Receptor and Hsp90: The Antiestrogen RU 58668 Induces a Protein Synthesis-Dependent Clustering of the Receptor in the Cytoplasm Mol. Endocrinol., June 1, 1998; 12(6): 842 - 854. [Abstract] [Full Text]

				J. I. Macgregor and V. C. Jordan Basic Guide to the Mechanisms of Antiestrogen Action Pharmacol. Rev., June 1, 1998; 50(2): 151 - 196. [Abstract] [Full Text] [PDF]

				S. Yeh, H. Miyamoto, H. Shima, and C. Chang From estrogen to androgen receptor: A new pathway for sex hormones in prostate PNAS, May 12, 1998; 95(10): 5527 - 5532. [Abstract] [Full Text] [PDF]

				Z. Li, J. L. Joyal, and D. B. Sacks Calmodulin Enhances the Stability of the Estrogen Receptor J. Biol. Chem., May 11, 2001; 276(20): 17354 - 17360. [Abstract] [Full Text] [PDF]

				M. T. Preisler-Mashek, N. Solodin, B. L. Stark, M. K. Tyriver, and E. T. Alarid Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-alpha Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E891 - E898. [Abstract] [Full Text] [PDF]