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J. Biol. Chem., Vol. 275, Issue 21, 15885-15894, May 26, 2000

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Identification of Selective Estrogen Receptor Modulators by Their Gene Expression Fingerprints^*

Deborah A. Zajchowski^§, Katalin Kauser^¶, Daguang Zhu, Lynn Webster, Sharon Aberle^¶, Frank A. White III^**, Hsiao-Lai Liu, Rhonda Humm, Jean MacRobbie, Phyllis Ponte, Christa Hegele-Hartung, Rudolf Knauthe, Karl-Heinrich Fritzemeier, Ron Vergona^§§, and Gabor M. Rubanyi^¶

From the Departments of  Cancer Research, ^¶ Cardiovascular Research,  Biologics Discovery Research, and ^§§ Animal Pharmacology, Berlex Biosciences, Richmond, California 94804 and  Schering Research Laboratories, Schering AG 13342 Berlin, Germany

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.

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