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

Mika Hilvo(University of Cambridge), Carsten Denkert(University of Cambridge), Laura Lehtinen(University of Cambridge), Berit Müller(University of Cambridge), Scarlet Brockmöller(University of Cambridge), Tuulikki Seppänen‐Laakso(University of Cambridge), Jan Budczies(University of Cambridge), Elmar Bucher(University of Cambridge), Laxman Yetukuri(University of Cambridge), Sandra Castillo(University of Cambridge), Emilia Berg(University of Cambridge), Heli Nygrén(University of Cambridge), Marko Sysi‐Aho(University of Cambridge), Julian L. Griffin(University of Cambridge), Oliver Fiehn(University of Cambridge), Sibylle Loibl(University of Cambridge), Christiane Richter-Ehrenstein(University of Cambridge), Cornelia Radke(University of Cambridge), Tuulia Hyötyläinen(University of Cambridge), Olli Kallioniemi(University of Cambridge), Kristiina Iljin(University of Cambridge), Matej Orešič(University of Cambridge)
Cancer Research
March 17, 2011
10.1158/0008-5472.can-10-3894
Cited by 535

Abstract

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-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.

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