This Article Full Text 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 Bentrem, D. Articles by Jordan, V. C. Search for Related Content PubMed PubMed Citation Articles by Bentrem, D. Articles by Jordan, V. C.

Distinct Molecular Conformations of the Estrogen Receptor Complex Exploited by Environmental Estrogens¹

Robert H. Lurie Comprehensive Cancer Center [D. B., J. E. F., S. T. P., H. L., S. P., V. C. J.] and Department of Surgery [D. B., S. P.], Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 [D. K.]; and Incyte, San Diego, California 92121 [J. W. Z.]

We have advanced the view that estrogens activate the estrogen receptor (ER) complex differently. A group of planar (estradiol, genistein, and coumestrol) and nonplanar (methoxychlor and its mono- and didemethylated phenolic metabolites) environmental estrogens, which are all full estrogens in MCF-7 breast cancer cell proliferation assays, was shown to segregate discretely into planar and nonplanar groups. These groups were delineated using a novel assay of mutant ER cDNAs stably transfected into MDA-MB-231 cells and the activation of the transforming growth factor target gene in situ that putatively describes the external shape of the ER complex. Planar compounds activate estrogen action through the two traditional activation functions (AFs), AF1 and AF2, in the ER. In contrast, nonplanar compounds can activate estrogen action through AF1 and the amino acids Asp-351 and Asp-538, which are exposed when helix 12 silences AF2. The observation that class I (planar) and class II (nonplanar) compounds have different mechanisms of estrogen action may have important implications for tissue selective modulation of the ER.

This article has been cited by other articles:

				C. J. Fabian and B. F. Kimler Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1644 - 1655. [Full Text] [PDF]

				C. Osipo, H. Liu, K. Meeke, and V. C. Jordan The Consequences of Exhaustive Antiestrogen Therapy in Breast Cancer: Estrogen-Induced Tumor Cell Death Experimental Biology and Medicine, September 1, 2004; 229(8): 722 - 731. [Abstract] [Full Text] [PDF]

				S. T. Pearce, H. Liu, I. Radhakrishnan, M. Abdelrahim, S. Safe, and V. C. Jordan Interaction of the Aryl Hydrocarbon Receptor Ligand 6-Methyl-1,3,8-trichlorodibenzofuran with Estrogen Receptor {alpha} Cancer Res., April 15, 2004; 64(8): 2889 - 2897. [Abstract] [Full Text] [PDF]