Researchers studying estrogen signaling were thrown a curve ball in 1993 when mice with knocked-out estrogen receptor genes failed to display the severe deficits expected in estrogen-dependent cardiovascular and bone functions.
Subsequent studies have cleared up some of the resulting questions, while raising other questions and new therapeutic possibilities as well.
The knockout mice were sterile, with abnormal reproductive organs and bone growth. But even their survival was something of a surprise, suggesting the existence of another estrogen receptor. A report on a human knockout a man with a mutated ER gene described similar findings. The patient was normal in most respects but had incomplete closure of bone ends, which contributed to his 6-foot-8-inch height.
In 1996, Jan-Åke Gustafsson, M.D., Ph.D., and colleagues at the Karolinska Institute in Huddinge, Sweden, cloned a novel receptor, designated ER beta. The "classical" ER was dubbed ER alpha.
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Estrogen receptor molecules form pairs dimers when they do their job of binding estrogen to activate gene transcription. The finding that ERs alpha and beta can pair up to form heterodimers suggests the two sometimes act in concert, and experts believe these heterodimers may modulate estrogen's effects in different tissues and under different conditions. Just how they work is far from clear. But as new findings emerge, conceptual models are being rebuilt.
Daring Hypothesis
"Quite a daring hypothesis that we nurture at the present time," Gustafsson said, "is that the two receptors represent almost a yin-yang principle.They have different effects that balance out each other. It often seems that ER beta sort of quenches or down-regulates the activities of ER alpha. Specifically, while alpha is typically involved in cell proliferation, beta appears to serve as a brake," he said.
Gustafsson believes, for example, that ER beta may suppress proliferation and prevent hyperplasia in the prostate. This is supported by observations that ER beta knockout mice develop prostatic hyperplasia, and that epithelial cells in the rat prostate have been found to express ER beta but not ER alpha.
If true, this hypothesis might even lend credence to anecdotal reports that eating certain plant products relieves benign prostatic hyperplasia in men, he said, because ER beta is especially good at binding phytoestrogens such as genistein and daidzein.
"Phytoestrogens are very good ligands for ER beta," he said. "We believe that many of the alleged effects of phytoestrogens, in terms of protection against breast and prostate cancer, could be due to their action on ER beta, leading to a decrease in proliferation."
Gail S. Prins, Ph.D., of the University of Illinois at Chicago, said the discovery of the new receptor was particularly significant for studies of the prostate and ovary. Scientists knew that the prostate is highly responsive to estrogen at certain stages of life, but were unable to find ERs there. It was assumed that estrogen must work indirectly in the prostate and also in the ovary, where researchers puzzled over the paucity of ERs.
It now seems likely that ER beta plays important roles in these tissues, and in rodent studies the highest levels of ER beta mRNA were found in ovary and prostate. Prins cautions, however, that "no one knows the genes it regulates; in fact, we don't know very many of the genes ER alpha regulates." She said that more studies are needed on the ER beta protein as opposed to mRNA.
ER beta raises another set of questions as well, Prins said. The finding that alpha and beta ERs bind 17-beta estradiol with about equal affinity "calls into question tons of data from binding studies done in the 1960s, '70s, and '80s," when the distinction between alpha and beta was unknown, she said. Investigators who assumed they were looking at ER alpha activity may instead have been seeing ER beta in some cases.
Kenneth S. Korach, Ph.D., of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and colleagues, including Gustafsson and Oliver Smithies, D. Phil., of the University of North Carolina, Chapel Hill, have made ER beta knockout mice and more recently, mice with both alpha and beta receptors KO'd. Both were able to survive, although like the alpha KO mice they showed a variety of abnormalities in estrogen-dependent functions.
"The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO," Korach and John F. Couse, Ph.D., also of NIEHS, write in the June 1999 Endocrine Reviews.
A study by Myles Brown, M.D., of the Dana-Farber Cancer Institute in Boston, and colleagues adds yet another layer of intricacy to estrogen signaling. Screening a library of rat prostate cDNA led Brown and co-workers to clone a variant ER beta gene that contains an added exon and is spliced differently than the original form.
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Superior SERMS
Researchers hope improved understanding of estrogen receptors and their multiple roles will lead to the discovery of selective estrogen receptor modulators that are superior to the existing SERMs, tamoxifen and raloxifene. Drug makers are searching for compounds with more specific receptor effects, although, Brown said, it is still unclear exactly which kinds of drugs would work best against which diseases.
"The ideal SERM," he said, "would be one that blocks the effects of estrogen in the breast and endometrium, where estrogens promote growth and potentially, cancer; one that has the same effect as estrogen in the cardiovascular system, where estrogen improves lipoprotein profiles and protects against atherosclerosis; and [one] in bone where it protects against osteoporosis." Estrogen also acts on the brain, and some data suggest it may help prevent Alzheimer's disease. The location of the ER beta gene may be important: it is on chromosome 14q, which is very close to a gene (presenilin 1) that is mutated in 50% of early-onset Alzheimer's cases.
A group led by the husband-and-wife team of Benita and John Katzenellenbogen, both Ph.D.s, at the University of Illinois, Urbana, has identified several compounds that are selective agonists or antagonists for either ER alpha or ER beta. And Gustafsson and partners have formed a biotech company, KaroBio, based in Huddinge. KaroBio is collaborating with Merck & Co., Inc., to develop agents to diagnose and treat conditions affected by estrogen receptors.
Similar reasoning underlies efforts to target drugs to proteins that act as co-regulatory factors in estrogen signaling. As with ERs, co-regulators differ in their expression patterns in different tissues, although the details are not fully understood.
"The idea is to find selective estrogen receptor ligands that stimulate the association with one but not the other co-regulators," Brown explained.
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