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Impact of Estrogen Receptor ß on Gene Networks Regulated by Estrogen Receptor in Breast Cancer Cells

Departments of Molecular and Integrative Physiology (E.C.C., J.F., B.S.K.), and Cell and Developmental Biology (B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and Women’s Health and Musculoskeletal Biology (B.K.), Wyeth Research, Collegeville, Pennsylvania 19426

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.

Two subtypes of the estrogen receptor (ER), ER and ERß, mediate the actions of estrogens, and although 70% of human breast cancers express ERß along with ER, little is known about the possible comodulatory effects of these two ERs. To investigate this, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing different levels of ERß, along with their endogenous ER, and have examined the effects of ERß and receptor occupancy, using ER subtype selective ligands, on genome-wide gene expression by microarray and pathway network analysis. ERß had diverse effects on gene expression, enhancing or counteracting ER regulation for distinct subsets of estrogen target genes. Strikingly, ERß in the absence of estradiol (E2), elicited the stimulation or suppression of many genes that were normally only regulated by ER with E2. In addition, ERß plus E2 elicited the expression of a unique group of genes that were not regulated by ER plus E2 alone. The expression of genes in many functional categories were modulated by ERß, with the greatest numbers associated with transcription factors and signal transduction pathways. Regulation of multiple components in the TGFß and semaphorin pathways, and of genes controlling cell cycle progression and apoptosis, may contribute to the suppression of cell proliferation observed with ERß. Our observations suggest that the relative levels of ERß and ER in breast cancers are likely to impact cell proliferation and the activities of diverse signaling pathways and their response to ER ligands and endocrine therapies.

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