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Increases in estrogen receptor‐α concentration in breast cancer cells promote serine 118/104/106‐independent AF‐1 transactivation and growth in the absence of estrogen
Author(s) -
Fowler Amy M.,
Solodin Natalia,
PreislerMashek Mara T.,
Zhang Ping,
Lee Adrian V.,
Alarid Elaine T.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0038com
Subject(s) - transactivation , estrogen receptor , estrogen receptor alpha , tamoxifen , cancer research , estrogen receptor beta , estrogen , endocrinology , biology , medicine , phosphorylation , transcription factor , receptor , breast cancer , chemistry , microbiology and biotechnology , cancer , gene , biochemistry
A common phenotype in breast cancer is the expansion of the estrogen receptor‐α (ER+) cell population and an inappropriate elevation of ERα protein, the latter predisposing patients for a poorer prognosis than those with lower levels of the receptor. A tetracycline‐inducible ERα overexpression model was developed in the MCF‐7 cell line to assess induction of endogenous gene activation and growth in response to elevations in ERα protein. Heightened levels of ERα 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 ERα 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 ERα concentration may provide a proliferative advantage by augmenting ERα 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‐α concentration in breast cancer cells promote serine 118/104/106‐independent AF‐1 transactivation and growth in the absence of estrogen. FASEB J. 18, 81–93 (2004)