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

被引：442

作者：

Hilvo, Mika ^{[1
]}

Denkert, Carsten ^{[2
]}

Lehtinen, Laura ^{[5
]}

Mueller, Berit ^{[2
]}

Brockmoeller, Scarlet ^{[2
]}

Seppanen-Laakso, Tuulikki ^{[1
]}

Budczies, Jan ^{[2
]}

Bucher, Elmar ^{[5
]}

Yetukuri, Laxman ^{[1
]}

Castillo, Sandra ^{[1
]}

Berg, Emilia ^{[1
]}

Nygren, Heli ^{[1
]}

Sysi-Aho, Marko ^{[1
]}

Griffin, Julian L. ^{[6
]}

Fiehn, Oliver ^{[7
]}

Loibl, Sibylle ^{[8
]}

Richter-Ehrenstein, Christiane ^{[3
]}

Radke, Cornelia ^{[4
]}

Hyotylainen, Tuulia ^{[1
]}

Kallioniemi, Olli ^{[5
]}

Iljin, Kristiina ^{[5
]}

Oresic, Matej ^{[1
]}

机构：

[1] VTT Tech Res Ctr Finland, FI-02044 Espoo, Finland

[2] Charite, Inst Pathol, Berlin, Germany

[3] Charite, Breast Canc Ctr, Berlin, Germany

[4] DRK Klinikum Berlin Kopenick, Inst Pathol, Berlin, Germany

[5] VTT Tech Res Ctr Finland, Turku, Finland

[6] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England

[7] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA

[8] GBG Forsch GmbH, German Breast Grp, Neu Isenburg, Germany

来源：

CANCER RESEARCH | 2011年 / 71卷 / 09期

关键词：

FATTY-ACID SYNTHASE; ACETYL-COA CARBOXYLASE; PROSTATE-CANCER; MASS-SPECTROMETRY; SYNTHESIS PATHWAY; CELLS; OVEREXPRESSION; EXPRESSION; GENE; INHIBITION;

D O I：

10.1158/0008-5472.CAN-10-3894

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 a), 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. Cancer Res; 71(9); 3236-45. (C) 2011 AACR.

引用

页码：3236 / 3245

页数：10

共 35 条

[1]

K-OPLS package: Kernel-based orthogonal projections to latent structures for prediction and interpretation in feature space [J].