1. Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor.
- Author
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Levenson AS, Svoboda KM, Pease KM, Kaiser SA, Chen B, Simons LA, Jovanovic BD, Dyck PA, and Jordan VC
- Subjects
- Breast Neoplasms drug therapy, Breast Neoplasms genetics, Culture Techniques, Estrogen Receptor alpha, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, Oligonucleotide Array Sequence Analysis, Receptors, Estrogen biosynthesis, Receptors, Estrogen genetics, Selective Estrogen Receptor Modulators metabolism, Substrate Specificity, Breast Neoplasms metabolism, Receptors, Estrogen metabolism, Selective Estrogen Receptor Modulators pharmacology
- Abstract
Selective Estrogen Receptor Modulators (SERMs) are a new class of drugsthat bind to estrogen receptor (ER) and elicit agonistic or antagonistic responses, depending on the target tissue. We have developed an in vitro system in which some SERMs (4-hydroxytamoxifen and resveratrol) demonstrate estrogenic response through wild-type (wt) ER, whereas others (raloxifene and GW7604) remain antiestrogenic. This system mimics the tamoxifen-resistant phenotype in clinic, when resistant tumors contain wtER. We used Atlas cDNA arrays to study gene expression profiles after ER activation by different SERMs in MDA-MB-231 human breast cancer cells stably transfected with wtER. Cells were treated with estradiol, four different SERMs, and the pure antiestrogen ICI 182,780. The obtained expression data were analyzed using GeneSpring software. Real-time reverse transcription-PCR was used to verify the array data. Our results showed that treatment with various compounds altered the expression of a diverse group of genes, revealing sets of overlapping genes that may represent a complex network of genes of interrelated signal transduction pathways. Sets of "agonistic" and "antagonistic" genes were identified on the basis of the known response to different SERMs. Further analysis of selected sets of genes revealed functionally related group of genes in each set, encoding proteins that were related to cell proliferation, survival, and apoptosis. Flow cytometry data indicated an antiapoptotic activity in cells treated with agonists versus apoptotic activity in cells treated with antagonists. A model for estradiol-like (survival) and antiestrogen-like (apoptosis) activities of SERMs on the basis of their gene expression profiles is suggested.
- Published
- 2002