title: Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via C/EBPβ and potentiates breast cancer progression.
abstract: A crucial role of the inflammatory lipid sphingosine-1-phosphate (S1P) in breast cancer aggressiveness has been reported. Recent clinical studies have suggested that C-reactive protein (CRP) has a role in breast cancer development. However, limited information is available on the molecular basis for the expression of CRP and its functional significance in breast cell invasion. The present study aimed to elucidate the molecular link between S1P and CRP during the invasive process of breast epithelial cells. This is the first report showing that transcription of CRP was markedly activated by S1P in breast cells. Our data suggest that not only S1P treatment but also the endogenously produced S1P may upregulate CRP in breast carcinoma cells. Transcription factors CCAAT/enhancer-binding protein beta and c-fos were required for S1P-induced CRP expression. Coupling of S1P3 to heterotrimeric Gαq triggered the expression of CRP, utilizing signaling pathways involving reactive oxygen species (ROS), Ca(2+) and extracellular signal-related kinases (ERKs). S1P-induced CRP expression was crucial for the transcriptional activation of matrix metalloproteinase-9 through ERKs, ROS and c-fos, leading to breast cell invasion. Using a xenograft mice tumor model, we demonstrated that S1P induced CRP expression both in vitro and in vivo. Taken together, our findings have revealed a molecular basis for S1P-induced transcriptional activation of CRP and its functional significance in the acquisition of the invasive phenotype of human breast epithelial cells under inflammatory conditions. Our findings may provide useful information on the identification of useful therapeutic targets for inflammatory breast cancer.
authors: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors: E-S
authors: ES
authors: Kim
authors: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors: Y
authors: Y
authors: Cha
authors: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors: M
authors: M
authors: Ham
authors: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors: J
authors: J
authors: Jung
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University, Seoul, Korea.
authors: S G
authors: SG
authors: Kim
authors: College of Medicine, Hanyang University, Seoul, Korea.
authors: S
authors: S
authors: Hwang
authors: Metabolic Health Research, TNO, CK Leiden, The Netherlands.
authors: R
authors: R
authors: Kleemann
authors: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors: A
authors: A
authors: Moon
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002097:C-Reactive Protein / Q000235:genetics*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D008246:Lysophospholipids; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; C060506:sphingosine 1-phosphate; D002097:C-Reactive Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D013110:Sphingosine; D002118:Calcium