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

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 express...

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Bibliographic Details
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
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-11-3069