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J. Biol. Chem., Vol. 275, Issue 21, 15885-15894, May 26, 2000
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From the Departments of 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.
Cancer Research,
¶ Cardiovascular Research,
Biologics Discovery Research,
and §§ Animal Pharmacology, Berlex Biosciences,
Richmond, California 94804 and 
Schering
Research Laboratories, Schering AG 13342 Berlin, Germany
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