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Altered Target Gene Regulation Controlled by Estrogen Receptor- Concentration

Department of Physiology, University of Wisconsin-Madison, Madison, Wisconsin 53706

Address all correspondence and requests for reprints to: Elaine T. Alarid, Ph.D., Department of Physiology, University of Wisconsin-Madison, 120 Service Memorial Institute, 1300 University Avenue, Madison, Wisconsin 53706. 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 component 3. The activation mechanism of ER under these conditions depends both on activation function-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-receptor interaction domain 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR

Coregulators:   SRC-1  |  GRIP1  |  AIB1

Ligands:   17β-Estradiol

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