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

Abstract

A common phenotype in breast cancer is the expansion of the estrogen receptor-alpha (ER+) cell population and an inappropriate elevation of ERalpha protein, the latter predisposing patients for a poorer prognosis than those with lower levels of the receptor. A tetracycline-inducible ERalpha overexpression model was developed in the MCF-7 cell line to assess induction of endogenous gene activation and growth in response to elevations in ERalpha protein. Heightened levels of ERalpha 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 ERalpha 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 ERalpha concentration may provide a proliferative advantage by augmenting ERalpha function regardless of ligand status.

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

“…It has been shown that steroid receptors, particularly those expressed in tumors, may become activated in the absence of cognate ligands (Weigel et al, 1995;Blaustein, 2004;Fowler et al, 2004). The data presented herein suggest that the same may be true for the AhR.…”

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

“…PRL-induced binding of ERa to the promoter determines co-activator recruitment and histone acetylation, both landmarks of receptor-mediated transcriptional activation. Increased ERa levels are common in breast cancer (Fabris et al, 1987;Holst et al, 2007) and have been associated with aberrant promoter occupancy, increased gene expression and cell proliferation in the absence of hormonal stimulation (Fowler et al, 2004). Because it has been reported that PRL increases ERa levels in breast cancer cells (Shafie and Brooks, 1977;Gutzman et al, 2004a), the stimulatory effect of PRL on the ER target genes could be due to ERa induction.…”

Differentiation of murine embryonic stem cells induces progesterone receptor gene expression

“…Cells were transiently transfected with the expression vector for HA-tagged human ERα, pUHD10-3-ER-HA, generously provided by Elaine T. Alarid, Department of Physiology, University of Wisconsin-Madison [33]. Cells were plated at 20,000 cells per well in a six-well plate in standard media containing LIF on day 0.…”