title: 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 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.
authors.affiliation: Bio and Process Technology, VTT Technical Research Centre of Finland, Espoo, Finland. mika.hilvo@vtt.fi
authors.forename: Mika
authors.initials: M
authors.lastname: Hilvo
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.forename: Laura
authors.initials: L
authors.lastname: Lehtinen
authors.forename: Berit
authors.initials: B
authors.lastname: Müller
authors.forename: Scarlet
authors.initials: S
authors.lastname: Brockmöller
authors.forename: Tuulikki
authors.initials: T
authors.lastname: Seppänen-Laakso
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Elmar
authors.initials: E
authors.lastname: Bucher
authors.forename: Laxman
authors.initials: L
authors.lastname: Yetukuri
authors.forename: Sandra
authors.initials: S
authors.lastname: Castillo
authors.forename: Emilia
authors.initials: E
authors.lastname: Berg
authors.forename: Heli
authors.initials: H
authors.lastname: Nygren
authors.forename: Marko
authors.initials: M
authors.lastname: Sysi-Aho
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Christiane
authors.initials: C
authors.lastname: Richter-Ehrenstein
authors.forename: Cornelia
authors.initials: C
authors.lastname: Radke
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D018450:Disease Progression; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D015996:Survival Rate
chemical_list: D010743:Phospholipids; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D064429:Fatty Acid Synthases