Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

作者：Mika Hilvo, Carsten Denkert, Laura E. Lehtinen, Berit Maria Müller, Scarlet F. Brockmöller, Tuulikki Seppänen‐Laakso, Jan Budczies, Elmar Bucher, Laxman Yetukuri, Sandra D. Castillo, Emilia Berg, Heli Nygrén, Marko Sysi‐Aho, Julian Leether Griffin, Oliver Fiehn, Sibylle Loibl, Christiane Richter-Ehrenstein, Cornelia Radke, Tuulia Hyötyläinen, Olli Kallioniemi, Kristiina Iljin, Matej Orešič · 发表于：Cancer Research · 年份：2011 · DOI：10.1158/0008-5472.can-10-3894 · 被引用次数：542 · 研究领域：Cancer, Lipids, and Metabolism、Metabolomics and Mass Spectrometry Studies、Cancer, Hypoxia, and Metabolism

Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induce...