Abstract
Clinical studies have shown that estrogen replacement therapy (ERT) reduces the incidence and severity of osteoporosis and cardiovascular disease in postmenopausal women. However, long term estrogen treatment also increases the risk of endometrial and breast cancer. The selective estrogen receptor (ER) modulators (SERMs) tamoxifen and raloxifene, cause antagonistic and agonistic responses when bound to the ER. Their predominantly antagonistic actions in the mammary gland form the rationale for their therapeutic utility in estrogen-responsive breast cancer, while their agonistic estrogen-like effects in bone and the cardiovascular system make them candidates for ERT regimens. Of these two SERMs, raloxifene is preferred because it has markedly less uterine-stimulatory activity than either estrogen or tamoxifen. To identify additional SERMs, a method to classify compounds based on differential gene expression modulation was developed. By analysis of 24 different combinations of genes and cells, a selected set of assays that permitted discrimination between estrogen, tamoxifen, raloxifene, and the pure ER antagonist ICI164384 was generated. This assay panel was employed to measure the activity of 38 compounds, and the gene expression fingerprints (GEFs) obtained for each compound were used to classify all compounds into eight groups. The compound's GEF predicted its uterine-stimulatory activity. One group of compounds was evaluated for activity in attenuating bone loss in ovariectomized rats. Most compounds with similar GEFs had similar in vivo activities, thereby suggesting that GEF-based screens could be useful in predicting a compound's in vivo pharmacological profile.
Highlights
Determining the function of proteins encoded by all human genes in normal and pathological states is a current challenge faced by the scientific community that the cloning and sequencing of a large percentage of the expressed human genomic sequences has been accomplished
To determine whether classification by gene expression fingerprints (GEFs) could provide a guide for selection of weak versus strong stimulators of the endometrium, we evaluated the uterine stimulatory activity of most of the compounds found in groups 2– 8
The results demonstrate that it is possible to group compounds based on differences and similarities in the pattern of gene expression changes that they elicit
Summary
Determining the function of proteins encoded by all human genes in normal and pathological states is a current challenge faced by the scientific community that the cloning and sequencing of a large percentage of the expressed human genomic sequences has been accomplished This effort to determine function will be facilitated by recent advances in the methodology used to simultaneously monitor the expression of hundreds to thousands of genes [1, 2] in various phenotypic states (e.g. normal versus neoplastic, diseased, or activated cells). To be useful in distinguishing SERMs, the cells and genes monitored in response to compound treatment should enable the generation of a different “gene expression fingerprint” (GEF) for estrogen, Tam, and Ral. Ideally, the resultant GEF should be able to predict the compound’s in vivo biological effects. The results demonstrate that the majority of compounds with similar GEFs have similar in vivo activities
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