Inflammatory Lipid Sphingosine‐1‐phosphate Upregulates c‐reactive Protein via C/EBPßß and Potentiates Breast Cancer Progression

Abstract

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 (C/EBPß) 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), Ca2+, and ERKs. S1P‐induced CRP expression was crucial for the transcriptional activation of matrix metalloproteinase (MMP)‐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.