Loss of the Ceramide Transfer Protein Augments EGF Receptor Signaling in Breast Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-06, Vol.72 (11), p.2855-2866
• Main Authors: HEERING, Johanna, WEIS, Nicole, KORTE, Thomas, HERRMANN, Andreas, OLAYIOYE, Monilola A, HOLEITER, Monika, NEUGART, Felix, STAEBLER, Annette, FEHM, Tanja N, BISCHOFF, Annabell, SCHILLER, Jurgen, DUSS, Stephan, SCHMID, Simone
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - chemistry; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement; ErbB Receptors - metabolism; ErbB Receptors - physiology; Female; Focal Adhesions; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Pharmacology. Drug treatments; Phospholipase D - physiology; Protein-Serine-Threonine Kinases - analysis; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-3069

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.