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Gene expression profiling studies of three SERMs and their conjugated estrogen combinations in human breast cancer cells: insights into the unique antagonistic effects of bazedoxifene on conjugated estrogens.

Abstract
Bazedoxifene (BZA), a new selective estrogen receptor modulator (SERM) was recently approved in Europe for the prevention and treatment of postmenopausal osteoporosis. Combination therapy using BZA and conjugated estrogens (CE) is currently in late stage development representing a new paradigm for the treatment of menopausal symptoms and prevention of osteoporosis. A GeneChip microarray study was designed to compare gene expression profiles of BZA to that of other SERMs, raloxifene (RAL) and lasofoxifene (LAS). In addition, we compared the gene expression profiles of the three SERMs in combination with CE, a mixture of 10 most abundant estrogens present in Premarin. According to the hierarchical clustering heat map analysis, gene clusters that specifically responded to CE treatments or SERM treatments were identified and gene lists sorted based on a set of cutoff filters. A group of genes differentially regulated by CE were also identified to be antagonized by BZA when comparing CE with the BZA+CE treatment. All three SERMs showed significant antagonistic effect against CE-stimulated cell proliferation, based on the MCF-7 cell proliferation assay and GeneChip data, with the order of antagonist activity being BZA>RAL>LAS. These results indicate that SERMs in combination with CE exhibit differential pharmacology, and therefore, combinations of other SERMs and estrogen preparations may not yield the same effects that are observed in clinic by pairing BZA with CE.
AuthorsKen C N Chang, Yihe Wang, Peter V N Bodine, Sunil Nagpal, Barry S Komm
JournalThe Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 118 Issue 1-2 Pg. 117-24 (Jan 2010) ISSN: 1879-1220 [Electronic] England
PMID19914376 (Publication Type: Journal Article)
CopyrightCopyright 2009 Elsevier Ltd. All rights reserved.
Chemical References
  • Estrogen Antagonists
  • Estrogens, Conjugated (USP)
  • Indoles
  • Pyrrolidines
  • Selective Estrogen Receptor Modulators
  • Tetrahydronaphthalenes
  • Lasofoxifene
  • Raloxifene Hydrochloride
  • Estradiol
  • bazedoxifene
Topics
  • Breast Neoplasms (metabolism, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cluster Analysis
  • Down-Regulation (genetics)
  • Estradiol (pharmacology)
  • Estrogen Antagonists (pharmacology)
  • Estrogens, Conjugated (USP) (antagonists & inhibitors, pharmacology)
  • Female
  • Gene Expression (drug effects, genetics)
  • Gene Expression Profiling
  • Humans
  • Indoles (pharmacology)
  • Oligonucleotide Array Sequence Analysis
  • Pyrrolidines (pharmacology)
  • Raloxifene Hydrochloride (pharmacology)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Selective Estrogen Receptor Modulators (pharmacology)
  • Signal Transduction (drug effects, genetics)
  • Tetrahydronaphthalenes (pharmacology)
  • Up-Regulation (genetics)

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