TY - JOUR
T1 - Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression
AU - Hilvo, Mika
AU - Denkert, C.
AU - Lehtinen, Laura
AU - Muller, B.
AU - Brockmoller, S.
AU - Seppänen-Laakso, Tuulikki
AU - Budczies, J.
AU - Bucher, Elmar
AU - Yetukuri, Laxman
AU - Castillo, Sandra
AU - Berg, Emilia
AU - Nygren, Heli
AU - Sysi-Aho, Marko
AU - Griffin, J. L.
AU - Fiehn, O.
AU - Loibl, S.
AU - Richter-Ehrenstein, C.
AU - Radke, C.
AU - Hyötyläinen, Tuulia
AU - Kallioniemi, Olli
AU - Iljin, Kristiina
AU - Oresic, Matej
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
U2 - 10.1158/0008-5472.CAN-10-3894
DO - 10.1158/0008-5472.CAN-10-3894
M3 - Article
SN - 0008-5472
VL - 71
SP - 3236
EP - 3245
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -
