This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rai, D. Articles by Katzenellenbogen, B. S. Search for Related Content PubMed PubMed Citation Articles by Rai, D. Articles by Katzenellenbogen, B. S.

Distinctive Actions of Membrane-Targeted Versus Nuclear Localized Estrogen Receptors in Breast Cancer Cells

Departments of Molecular and Integrative Physiology (D.R., A.F., J.F., B.S.K.) and Cell and Structural Biology (A.E.C., B.S.K.), University of Illinois and College of Medicine, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}uiuc.edu.

Estrogens regulate multiple activities in breast cancer cells, including proliferation. Whereas these hormones are most commonly known to regulate gene transcription through direct interaction with estrogen receptors (ERs) and with specific DNA sequences of target genes, recent studies show that ER also activates a number of rapid signaling events that are initiated at the cell membrane. To study the membrane-initiated effects of estrogen and separate them from the activities initiated by the nuclear localized ER in human breast cancer cells, we generated MDA-MB-231 breast cancer cell lines that have stably integrated either the wild-type nuclear form of ER (WT-ER) or a modified, membrane-targeted ER (MT-ER) that lacks a nuclear localization sequence and is dually acylated with a myristoylation sequence at the N terminus and a palmitoylation sequence at the C terminus. We demonstrate that MT-ER is membrane localized in the absence of estradiol (E2), showing punctate membrane and cytoplasmic speckles after E2 exposure. In contrast to WT-ER, MT-ER was not down-regulated by E2 or by antiestrogen ICI 182,780 exposure, and MT-ER failed to regulate endogenous E2-responsive genes highly up-regulated by WT-ER. Cells expressing MT-ER showed a greater serum response element-mediated transcriptional response that was partially inhibited by antiestrogen ICI 182,780. The MT-ER and WT-ER differentially altered ERK1/2 and Akt activities and the proliferation of breast cancer cells in response to E2. Hence, this study reveals distinct actions of the MT-ER vs. the WT-ER in effecting estrogen actions in breast cancer cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

This article has been cited by other articles:

				A. A. Kazi, K. H. Molitoris, and R. D. Koos Estrogen Rapidly Activates the PI3K/AKT Pathway and Hypoxia-Inducible Factor 1 and Induces Vascular Endothelial Growth Factor A Expression in Luminal Epithelial Cells of the Rat Uterus Biol Reprod, August 1, 2009; 81(2): 378 - 387. [Abstract] [Full Text] [PDF]

				K. Azuma, T. Urano, K. Horie-Inoue, S.-i. Hayashi, R. Sakai, Y. Ouchi, and S. Inoue Association of Estrogen Receptor {alpha} and Histone Deacetylase 6 Causes Rapid Deacetylation of Tubulin in Breast Cancer Cells Cancer Res., April 1, 2009; 69(7): 2935 - 2940. [Abstract] [Full Text] [PDF]

				B. Cinar, N. K. Mukhopadhyay, G. Meng, and M. R. Freeman Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains J. Biol. Chem., October 5, 2007; 282(40): 29584 - 29593. [Abstract] [Full Text] [PDF]

				X. Jiang, J. L. Benovic, and P. B. Wedegaertner Plasma Membrane and Nuclear Localization of G Protein coupled Receptor Kinase 6A Mol. Biol. Cell, August 1, 2007; 18(8): 2960 - 2969. [Abstract] [Full Text] [PDF]

				A. Zheng, A. Kallio, and P. Harkonen Tamoxifen-Induced Rapid Death of MCF-7 Breast Cancer Cells Is Mediated via Extracellularly Signal-Regulated Kinase Signaling and Can Be Abrogated by Estrogen Endocrinology, June 1, 2007; 148(6): 2764 - 2777. [Abstract] [Full Text] [PDF]

				K. Lehnes, A. D. Winder, C. Alfonso, N. Kasid, M. Simoneaux, H. Summe, E. Morgan, M. C. Iann, J. Duncan, M. Eagan, et al. The Effect of Estradiol on in Vivo Tumorigenesis Is Modulated by the Human Epidermal Growth Factor Receptor 2/Phosphatidylinositol 3-Kinase/Akt1 Pathway Endocrinology, March 1, 2007; 148(3): 1171 - 1180. [Abstract] [Full Text] [PDF]

				S. Kousteni, M. Almeida, L. Han, T. Bellido, R. L. Jilka, and S. C. Manolagas Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor Mol. Cell. Biol., February 15, 2007; 27(4): 1516 - 1530. [Abstract] [Full Text] [PDF]

				N. Vasudevan and D. W. Pfaff Membrane-Initiated Actions of Estrogens in Neuroendocrinology: Emerging Principles Endocr. Rev., February 1, 2007; 28(1): 1 - 19. [Abstract] [Full Text] [PDF]

				R. M. Drenan, C. A. Doupnik, M. Jayaraman, A. L. Buchwalter, K. M. Kaltenbronn, J. E. Huettner, M. E. Linder, and K. J. Blumer R7BP Augments the Function of RGS7{middle dot}Gbeta5 Complexes by a Plasma Membrane-targeting Mechanism J. Biol. Chem., September 22, 2006; 281(38): 28222 - 28231. [Abstract] [Full Text] [PDF]

				M. Almeida, L. Han, C. A. O'Brien, S. Kousteni, and S. C. Manolagas Classical Genotropic Versus Kinase-Initiated Regulation of Gene Transcription by the Estrogen Receptor {alpha} Endocrinology, April 1, 2006; 147(4): 1986 - 1996. [Abstract] [Full Text] [PDF]

				W. R. Harrington, S. H. Kim, C. C. Funk, Z. Madak-Erdogan, R. Schiff, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Estrogen Dendrimer Conjugates that Preferentially Activate Extranuclear, Nongenomic Versus Genomic Pathways of Estrogen Action Mol. Endocrinol., March 1, 2006; 20(3): 491 - 502. [Abstract] [Full Text] [PDF]