Genomics of Signaling Crosstalk of Estrogen Receptor α in Breast Cancer Cells

Autor: Didier Picard, Peter Dudek
Rok vydání: 2008
Předmět:
Estrogen Receptor alpha/genetics/metabolism
Cell signaling
Breast Neoplasms/drug therapy/genetics/metabolism
Transcription
Genetic
medicine.drug_class
lcsh:Medicine
Estrogen receptor
Breast Neoplasms
Biology
Bioinformatics
Molecular Biology/Translational Regulation
ddc:570
Cell Line
Tumor
Cyclic AMP
medicine
Humans
Genetics and Genomics/Genomics
lcsh:Science
Transcription factor
Oligonucleotide Array Sequence Analysis
Regulation of gene expression
Tamoxifen/pharmacology/therapeutic use
Multidisciplinary
lcsh:R
Estrogen Receptor alpha
Genetics and Genomics/Gene Expression
Estrogens
Cyclic AMP/physiology
Genomics
Receptor Cross-Talk
Genetics and Genomics/Gene Function
Tamoxifen
Genetics and Genomics/Disease Models
Estrogen
Cancer research
Estrogens/physiology
lcsh:Q
Transcription
Genetic/physiology
Signal transduction
Estrogen receptor alpha
hormones
hormone substitutes
and hormone antagonists
Research Article
Signal Transduction
medicine.drug
Zdroj: PLOS ONE, Vol. 3, No 3 (2008) P. e1859
PLoS ONE
PLoS ONE, Vol 3, Iss 3, p e1859 (2008)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0001859
Popis: BACKGROUND: The estrogen receptor alpha (ERalpha) is a ligand-regulated transcription factor. However, a wide variety of other extracellular signals can activate ERalpha in the absence of estrogen. The impact of these alternate modes of activation on gene expression profiles has not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: We show that estrogen, growth factors and cAMP elicit surprisingly distinct ERalpha-dependent transcriptional responses in human MCF7 breast cancer cells. In response to growth factors and cAMP, ERalpha primarily activates and represses genes, respectively. The combined treatments with the anti-estrogen tamoxifen and cAMP or growth factors regulate yet other sets of genes. In many cases, tamoxifen is perverted to an agonist, potentially mimicking what is happening in certain tamoxifen-resistant breast tumors and emphasizing the importance of the cellular signaling environment. Using a computational analysis, we predicted that a Hox protein might be involved in mediating such combinatorial effects, and then confirmed it experimentally. Although both tamoxifen and cAMP block the proliferation of MCF7 cells, their combined application stimulates it, and this can be blocked with a dominant-negative Hox mutant. CONCLUSIONS/SIGNIFICANCE: The activating signal dictates both target gene selection and regulation by ERalpha, and this has consequences on global gene expression patterns that may be relevant to understanding the progression of ERalpha-dependent carcinomas.
Databáze: OpenAIRE
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