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.
Highlights
An early and universal feature of tumors is the activation of lipid metabolism, and, the term "lipogenic phenotype" has been coined to describe the activation of the lipogenic enzymes in the malignant processes [1]
The results indicate that the de novo synthesized fatty acids incorporated into the membrane phospholipids are increased in tumors as compared with healthy tissue, and this process further increases during cancer progression, that is, in ERÀ and grade 3 tumors
The results indicated that ELOVL1, fatty acid synthase (FASN), SCD, and SCAP siRNAs silenced their target genes efficiently (>50% of the scrambled control), whereas for acetyl-CoA carboxylase a (ACACA), THRSP, and INSIG1 silencing was only partial
Summary
An early and universal feature of tumors is the activation of lipid metabolism, and, the term "lipogenic phenotype" has been coined to describe the activation of the lipogenic enzymes in the malignant processes [1]. The lipid metabolism of cancer has been predominantly investigated at the level of genes and many of these have been shown to affect tumorigenesis. The field has gained additional interest, as accumulating evidence suggests that cancer and metabolic diseases are connected at the level of lipid metabolism [2]. Human cells have 2 sources of fatty acids; diet or de novo synthesis [1]. The role of de novo fatty acid synthesis is usually minor, as the cells primarily rely on dietary fatty acids. A few healthy tissues, such as liver or adipose tissue, and specific physiologic processes, such as endometrial cell proliferation
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