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Submitted on July 13, 2005
Accepted on September 14, 2005
Concentration
Department of Physiology, University of Wisconsin-Madison, Madison, WI 53706, USA
* To whom correspondence should be addressed. E-mail: alarid{at}physiology.wisc.edu.
Estrogen receptor-
(ER) is a transcriptional activator whose concentration is tightly regulated by the cellular environment. In breast tumors of postmenopausal women, elevated receptor concentrations can be associated with negative clinical outcomes, yet it remains poorly understood how such high levels impact ER function. We previously demonstrated that high nuclear concentrations of ER in breast cancer cells bypass the requirement for ligand and are sufficient to activate transcription and accelerate proliferation. Here, we extended those studies and asked whether the transcriptional targets and activation mechanism are similar or different from that of estrogen-stimulated ER. We found that at elevated levels, ER activated but could not repress known estrogen-responsive genes. Moreover, the set of activated genes was expanded to include the uterine-restricted target gene, complement C3. The activation mechanism of ER under these conditions depends both on AF-1 and residues in the proximal region of the ligand-binding domain. Mutations of aspartate 351 and leucine 372 can inhibit ER transcriptional activity gained at high concentrations and discriminate "concentration-inducible" ER function from that induced by estrogen. Moreover, we demonstrate that at high levels, ER stimulates transcription without recruiting steroid receptor coactivator-3 and without interference by a Gal4-RID box fusion protein containing LxxLL motifs, further distinguishing this mode of regulation from known activation mechanisms. Together these results demonstrate that the concentration of receptor in breast cancer cells can influence the pattern of target gene expression through a noncanonical activation mechanism.
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