Edited by: Paul Smaglik
G.G.J.M. Kuiper, B. Carlsson, K. Grandien, E. Enmark, J. Haggblad, S. Nilsson, J.A. Gustafsson, "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and ß ," Endocrinology, 138:863-70, March 1997. (Cited in more than 265 papers since publication)
Comments by Jan-Åke Gustafsson, professor and chairman, Department of Medical Nutrition, Karolinska Institute, Huddinge, Sweden, and chairman, Department of Biosciences at Novum, Huddinge University Hospital, Huddinge, Sweden
Before April 1996, researchers studying estrogen binding only saw half the picture. Then Jan-Åke Gustafsson reported a novel estrogen receptor (ER), ER ß , and he and colleagues formally published their results.1 This 1997 follow-up paper compared ligand-binding specificities of the classical ER-alpha and the novel ERß. "The homology in the ligand-binding domain between the two receptors was about 58 percent, so both differences and similarities were to be expected," he comments.
This paper confirmed those suspicions. While Gustafsson and colleagues observed several examples of ligands binding to both receptors, they also noticed some striking instances of specificity; for instance, the phytoestrogen genistein binds about 100 times more efficiently to ERß than to ER-alpha . "This is potentially highly exciting, since ERß might be described as the 'phytoestrogen receptor'; in other words, phytoestrogens might represent examples of physiological ligands for ERß," Gustafsson notes. "Another putative ligand, particularly in males, is 5-alpha-androstane-3ß, 17ß-diol, which binds better to ERß than to ER-alpha ."
Gustafsson suspects that any research reporting on the mechanism of estrogen's action will attract attention. "This is a very hot topic in view of its implications--especially for women's health." This research may be especially relevant to the field of hormone replacement therapy. While treatment with estrogens and progestins alleviates some postmenopausal symptoms, "it is not without risk," Gustafsson cautions. "Higher incidences of breast and endometrial carcinoma have been reported following hormone replacement therapy."
Applying the knowledge of ERß biology and ligand-binding characteristics might help to develop novel pharmaceutical agents without those side effects. That knowledge--and therefore the possibility for better therapy--has advanced since this 1997 paper. "We [now] have a quite clear view about the distribution of ERß in the organism," Gustafsson comments. "We know, for instance, that ERß appears to be a major estrogen receptor, perhaps as important [as] or more important quantitatively than ER-alpha."
Within the last year, Gustafsson and collaborators have begun to unravel the particular biology of ER ß by using transgenic mice. They have observed a "plethora" of interesting phenotypes in ERß-/- mice developed with Oliver Smithies in Research Triangle Park, Chapel Hill, N.C. For instance, the ERß-/- female mice are 80 percent infertile owing to follicular arrest and anovulation. "We are currently investigating other interesting phenotypes."
Gustafsson suspects that more biological differences between ER-alpha and ERß will emerge--in both in vitro and in vivo actions. "The ERß-/- animals will continue to generate interesting data for many years," he predicts. "We will be able to see whether our notion that ER-alpha and ERß represent a yin/yang principle in estrogen mechanism of action is correct." If ERß helps put the brakes on cell proliferation, as he suspects, antitumor agents based on their ability to specifically interact with ERß could be developed. Such drugs might be of use in treatment of prostate cancer and mammary cancer.
Other intriguing questions remain. "Since estrogens influence mood and behavior, it would be interesting to see which of the two receptors is specifically associated with a particular behavior," Gustafsson comments. He also suspects that altering the quantification process of estrogen receptors in breast tumors holds potential. "The current practice [of separating] breast cancer patients into receptor-positive and receptor-negative patients and letting this distinction determine the therapeutic strategy (antihormone therapy versus irradiation and cytostatic agents) might be questionable, because commercially available immunoassays only seem to detect ER-alpha," Gustafsson comments. "Since ERß might well indicate favorable response to antihormone treatment we should presumably gain by complementing currently performed assays with ERß measurements." That adjustment might considerably increase the predictive and prognostic value of receptor assays in breast cancer, he concludes.