Amy M. Fowler 1999-2007
Transitional Year
Gunderson Luthern Medical Foundation, La Crosse, WI
South Dakota State University 1999
Cellular & Molecular Biology PhD 2005
Elaine Alarid
Concentration-Dependent Estrogen Receptor-Alpha Transcriptional Function in Breast Cancer
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A common phenotype of the majority of breast cancers is elevated cellular expression of estrogen receptor-alpha (ER-alpha). Why tumors expressing the highest levels of ER-alpha protein correlate with poor patient prognosis and reduced response to anti-hormone therapy is currently not understood. The studies presented here asked how such increases influence ER-alpha transactivation and mitogenic function. Contrary to expectation, elevated ER-alpha concentration had only a modest impact on estrogen-dependent transcription, but rather it significantly increased receptor-mediated gene activation in the absence of ligand. This was accompanied by enhanced anchorage-dependent and -independent breast cancer cell growth in the absence of estrogen. We define hormone-independent function gained at elevated levels of receptor as concentration-dependent ER-alpha activity. Investigation into the mechanism underlying this activity revealed a novel mode of receptor activation. Concentration-dependent receptor transactivation involves the N- and C-terminal regions of ER-alpha, but not phosphorylation of activation function-1, cross-talk with mitogen-activated protein kinase signaling, or p160 coactivators. Mutational analyses identified three residues (D351, L372, and L507) that discriminate concentration-dependent from estrogen-dependent ER-alpha activity. High levels of ER-alpha increased receptor occupancy at endogenous gene promoters, which prompted us to ask whether concentration-dependent ER-alpha activity might also alter receptor target gene specificity. We found that concentration-dependent ER-alpha function induced activation of genes known to be up-regulated by estrogen, but failed to repress down-regulated targets despite receptor binding to both promoter types. We also observed expansion of ER-alpha targets to include the uterine-specific, complement C3 gene, under these conditions. The work presented here highlights the key role ER-alpha protein concentration plays in controlling the mechanism of receptor transcriptional activation and its consequence on target gene regulation. Our results suggest that high levels of receptor in breast cancer cells may provide a selective advantage by facilitating hormone-independent, tamoxifen-insensitive ER-alpha activity. This aberrant receptor function, in turn, leads to alterations in the gene expression profile through gene activation, loss of gene repression, and expansion of target genes, which may ultimately contribute to the enhanced growth properties observed in malignant cells. These results are therefore of potential clinical importance toward improved diagnosis and therapy of hormone-independent ER-positive breast tumors. |
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| Thesis Publications |
- Fowler AM, Solodin NM, Valley CC, Alarid ET. Altered target gene regulation controlled by estrogen receptor-alpha concentration. Mol Endocrinol. 2006 20:291-301, 2006.
- Fowler AM, Solodin NM, Valley CC, Alarid ET. Altered target gene regulation controlled by estrogen receptor-{alpha} concentration. Mol Endocrinol, Epub ahead of print, PMID: 16179380, 2005.
- Valley CC, Metivier R, Solodin NM, Fowler AM, Mashek MT, Hill L, Alarid ET. Differential regulation of estrogen-inducible proteolysis and transcription by the estrogen receptor alpha N terminus. Mol Cell Biol. 25:5417-28, 2005.
- Fowler AM, Solodin N, Preisler-Mashek MT, Zhang P, Lee AV, Alarid ET. 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.FASEB J 18:81–93, 2004.
- Fowler AM, Alarid ET. Dynamic control of nuclear receptor transcription. Science's STKE 2004:51, 2004.
- Fowler AM, Alarid ET. Nuclear receptor and transcriptional complex cycles. Science's STKE 2004:11, 2004.
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