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

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 palmitatecontaining 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 cleavageactivating 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. Ó2011 AACR.

Influence of environmental medium on membrane fatty acid composition of Reuber H35 hepatoma cells

“…SFA are less susceptible to lipid peroxidation, so they prevent the oxidative damage. Studies have correlated the increase of a saturated phosphatidylcholine with progression of breast cancer (Hilvo et al 2011). Lipids in cancer cells have key functions as signaling molecules or introducing posttranslational modifications in proteins.…”

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

“…Small molecules and gene silencing (e.g. acetyl-CoA carboxylase alpha) were shown to be effective in inhibiting cancer cell proliferation and viability in vitro [77][78][79]. However, most experiments performed in monolayer cancer cell cultures do not accurately reflect the conditions found in in vivo, where the intercellular contact, tumor dynamics and overall heterogeneous microenvironment Fig.…”

Blockade of B-cell-activating factor signaling enhances hepatic steatosis induced by a high-fat diet and improves insulin sensitivity

“…30 Furthermore, inhibition of ACS amplifies antitumor effects. 31 The data in this study indicated that BAFF-R signaling on hepatocytes may have a role in the development and progression of liver cancer; nonetheless, further studies are necessary to substantiate this conclusion.…”