1. Loss of the ceramide transfer protein augments EGF receptor signaling in breast cancer.
- Author
-
Heering J, Weis N, Holeiter M, Neugart F, Staebler A, Fehm TN, Bischoff A, Schiller J, Duss S, Schmid S, Korte T, Herrmann A, and Olayioye MA
- Subjects
- Breast Neoplasms chemistry, Breast Neoplasms pathology, Cell Line, Tumor, Cell Movement, ErbB Receptors metabolism, Female, Focal Adhesions, Humans, Phospholipase D physiology, Protein Serine-Threonine Kinases analysis, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins c-akt metabolism, Breast Neoplasms metabolism, ErbB Receptors physiology, Protein Serine-Threonine Kinases physiology, Signal Transduction
- Abstract
Triple-negative breast cancers (TNBC) are especially refractory to treatment due to their negative hormone receptor and ErbB2/HER2 status. Therefore, the identification of cancer-associated deregulated signaling pathways is necessary to develop improved targeted therapies. Here, we show that expression of the ceramide transfer protein CERT is reduced in TNBCs. CERT transfers ceramide from the endoplasmic reticulum to the Golgi complex for conversion into sphingomyelin (SM). We provide evidence that by regulating cellular SM levels, CERT determines the signaling output of the EGF receptor (EGFR/ErbB1), which is upregulated in approximately 70% of TNBCs. CERT downregulation in breast cancer cells enhanced ErbB1 lateral mobility, ligand-induced autophosphorylation, internalization, and chemotaxis. Together, our findings provide a link between lipid metabolism at the Golgi with signaling at the plasma membrane, thereby implicating CERT loss in the progression of TNBCs., (©2012 AACR)
- Published
- 2012
- Full Text
- View/download PDF