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Increases in estrogen receptor- concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen

Department of Physiology, University of Wisconsin-Madison, Madison, Wisconsin, USA; and
^* The Breast Center and Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

¹Correspondence: Department of Physiology, 120 Service Memorial Institute, 1300 University Ave., Madison, WI 53706, USA. E-mail: alarid{at}physiology.wisc.edu

A common phenotype in breast cancer is the expansion of the estrogen receptor- (ER+) cell population and an inappropriate elevation of ER protein, the latter predisposing patients for a poorer prognosis than those with lower levels of the receptor. A tetracycline-inducible ER overexpression model was developed in the MCF-7 cell line to assess induction of endogenous gene activation and growth in response to elevations in ER protein. Heightened levels of ER resulted in aberrant promoter occupancy and gene activation in the absence of hormone, which was independent of ligand and AF-2 function. This increased receptor activity required the amino-terminal A/B domain and was not inhibited by tamoxifen, which supports an enhancement of AF-1 function, yet was independent of serine-104, 106, and 118 phosphorylation. Ligand-independent transcription was accompanied by an increase in growth in the absence of hormonal stimulation. The results suggest that elevated levels of ER in breast cancer cells can result in activation of receptor transcriptional function in a manner distinct from classical mechanisms that involve ligand binding or growth factor-induced phosphorylation. Further, they describe a potential mechanism whereby increases in ER concentration may provide a proliferative advantage by augmenting ER function regardless of ligand status.—Fowler, A. M., Solodin, N., Preisler-Mashek, M. T., Zhang, P., Lee, A. V., Alarid, E. T. Increases in estrogen receptor- concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen.

Key Words: nuclear receptor • steroid hormone • transcription • proliferation • ligand-independent

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