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Submitted on May 9, 2005
Accepted on November 15, 2005
Department of Molecular and Integrative Physiology, Department of Chemistry, and Department of Cell and Developmental Biology, University of Illinois, Urbana, IL, 61801; Department of Medicine, Breast Center, Baylor College of Medicine, Houston, Texas, 77030
* To whom correspondence should be addressed. E-mail: katzenel{at}uiuc.edu.
Estrogenic hormones are classically thought to exert their effects by binding to nuclear estrogen receptors (ERs) and altering target gene transcription, but estrogens can also have non-genomic effects through rapid activation of membrane-initiated kinase cascades. The development of ligands that selectively activate only the non-genomic pathways would provide useful tools to investigate the significance of these pathways. We have prepared large, abiotic, non-degradable poly(amido)amine (PAMAM) dendrimer macromolecules that are conjugated to multiple estrogen molecules through chemically robust linkages. Because of their charge and size, these estrogen-dendrimer conjugates (EDCs) remain outside the nucleus. They stimulate ERK, Shc and Src phosphorylation in MCF-7 breast cancer cells at low concentrations, yet they are very ineffective in stimulating transcription of endogenous estrogen target genes, being ca. 10,000-fold less potent than estradiol in genomic actions. In contrast to estradiol, EDC was not effective in stimulating breast cancer cell proliferation. Because these EDC ligands activate non-genomic activity at concentrations at which they do not alter the transcription of estrogen target genes, they should be useful in studying extranuclear initiated pathways of estrogen action in a variety of target cells.
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