Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin.
Obesity is a risk factor for breast cancer in postmenopausal women. Leptin, an adipocyte-derived cytokine, elicits proliferative effects in some cell types and potentially stimulates the growth of mammary epithelium. Here we show that leptin induced time- and dose-dependent signal transducer and activator of transcription 3 (STAT3) phosphorylation and extracellular ... signal-regulated kinase (ERK) 1/2 kinase activation in breast carcinoma cells. Blocking STAT3 phosphorylation with a specific inhibitor, AG490, abolished leptin-induced proliferation of MCF-7 cells, whereas blocking ERK1/2 activation by a specific ERK1/2 kinase inhibitor, U0126, did not result in any significant changes in leptin-induced cell proliferation. Our experiments also showed that one member of the p160 family of steroid receptor coactivators, steroid receptor coactivator (SRC)-1, but not glucocorticoid receptor interacting protein 1 (GRIP1) or amplified in breast cancer 1 (AIB1), also functioned in gene transactivation in response to leptin treatment. Glutathione S-transferase pull-down experiments showed that SRC-1 physically interacted with the activation domain of STAT3 and that chromatin immunoprecipitation experiments detected the occupancy of SRC-1, but not GRIP1 or AIB1, on the promoter of STAT3 target genes. Our experiments collectively showed that SRC-1 is involved in STAT3 signaling pathway that is implicated in leptin-stimulated cell growth.
Mesh Terms:
Breast Neoplasms, Carrier Proteins, Cell Division, Cell Line, Tumor, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, myc, Histone Acetyltransferases, Humans, Leptin, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Nerve Tissue Proteins, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivator 3, Promoter Regions, Genetic, Receptors, AMPA, Receptors, Leptin, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcriptional Activation
Breast Neoplasms, Carrier Proteins, Cell Division, Cell Line, Tumor, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, myc, Histone Acetyltransferases, Humans, Leptin, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Nerve Tissue Proteins, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivator 3, Promoter Regions, Genetic, Receptors, AMPA, Receptors, Leptin, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcriptional Activation
Cancer Res.
Date: Aug. 15, 2004
PubMed ID: 15313931
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