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Research focusing on why estrogenic hormones produce differing results

er were more susceptible to getting uterine cancer. Other research, conducted at Illinois by food scientist William Helferich, has shown that the soy phytoestrogen genestein in doses similar to that found in supplements may negate the ability of tamoxifen to stop cancer redevelopment. Many women take soy supplements to control hot flashes.

The discovery in 1996 of a second estrogen receptor, or binding protein, began to rewrite conventional wisdom. Instead of just one receptor, now known as ER-alpha, researchers began studying the second one, ER-beta. ER-alpha is predominant in the uterus, liver, mammary gland, bone and cardiovascular systems; ER-beta is most expressed in the prostate, ovary and urinary tract.

Researchers also have found that many estrogen-responsive genes don't have estrogen response elements -- long considered the cornerstone of estrogen receptor binding and transcription. Instead, as in the human progesterone receptor gene, they have multiple binding sites for activator proteins such as the four regions identified in Nardulli's lab.

The four regions in progesterone receptor gene are known as AP-1 and Sp1 sites. The Sp1 sites, Nardulli said, are "pretty potent activators that get transcription going" when exposed to most of the hormones tested. The AP-1 sites by themselves were weak -- responsive somewhat to estrogen but not to the other hormones. Mutating an AP-1 site in the context of a larger gene region dramatically reduces transcription. Her lab's findings also supported previous evidence that ER-alpha is much more potent than ER-beta.

"Turning on the expression of genes in a cell is not like turning on a light switch, because you have many different estrogen responsive genes in one cell," Nardulli said. "So, do you want to turn on all the genes to the same extent, or do you want to differentially regulate them? What researchers really would like to do is develop a hormone drug -- a ligand -- that targets
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Contact: Jim Barlow, Life Sciences Editor
jebarlow@uiuc.edu
217-333-5802
University of Illinois at Urbana-Champaign
11-Feb-2005


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