Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action.
Estrogenic hormones are classically thought to exert their effects by binding to nuclear estrogen receptors and altering target gene transcription, but estrogens can also have nongenomic effects through rapid activation of membrane-initiated kinase cascades. The development of ligands that selectively activate only the nongenomic pathways would provide useful tools to investigate the significance of these pathways. We have prepared large, abiotic, nondegradable poly(amido)amine 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 approximately 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 nongenomic 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.
Harrington
William R
WR
University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704, USA.
Kim
Sung Hoon
SH
Funk
Cory C
CC
Madak-Erdogan
Zeynep
Z
Schiff
Rachel
R
Katzenellenbogen
John A
JA
Katzenellenbogen
Benita S
BS
D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D050091:Dendrimers; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016678:Genome / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D012235:Rhodamines / Q000737:chemistry; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D050091:Dendrimers; D004967:Estrogens; C104700:PAMAM Starburst; D011073:Polyamines; D011960:Receptors, Estrogen; D012235:Rhodamines; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004958:Estradiol; C005358:tetramethylrhodamine; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases