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.
Yin
Na
N
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
Wang
Dan
D
Zhang
Hua
H
Yi
Xia
X
Sun
Xiaojing
X
Shi
Bin
B
Wu
Huijian
H
Wu
Ge
G
Wang
Xinjuan
X
Shang
Yongfeng
Y
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D016259:Genes, myc; D051548:Histone Acetyltransferases; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D011401:Promoter Regions, Genetic; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491310:GRIP1 protein, human; C515448:LEPR protein, human; D020738:Leptin; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases