Identification of selective estrogen receptor modulators by their gene expression fingerprints

Clinical studies have shown that estrogen replacement therapy (ERT) reduces the incidence and severity of osteoporosis and cardiovascular disease in p ostmenopausal women. However, long term estrogen treatment also increases t he risk of endometrial and breast cancer. The selective estrogen receptor ( ER) modulators (SERMs) tamoxifen and raloxifene, cause antagonistic and ago nistic responses when bound to the ER, Their predominantly antagonistic act ions in the mammary gland form the rationale for their therapeutic utility in estrogen-responsive breast cancer, while their agonistic estrogen-like e ffects in bone and the cardiovascular system make them candidates for ERT r egimens. Of these two SERMs, raloxifene is preferred because it has markedl y less uterine-stimulatory activity than either estrogen or tamoxifen, To i dentify additional SERMs, a method to classify compounds based on different ial gene expression modulation was developed. By analysis of 24 different c ombinations of genes and cells, a selected set of assays that permitted dis crimination between estrogen, tamoxifen, raloxifene, and the pure ER antago nist ICI164384 was generated. This assay panel was employed to measure the activity of 38 compounds, and the gene expression fingerprints (GEFs) obtai ned 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 ovariec tomized rats. Most compounds with similar GEFs had similar in vivo activiti es, thereby suggesting that GEF-based screens could be useful in predicting a compound's in vivo pharmacological profile.