Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression

Mika Hilvo, C. Denkert, Laura Lehtinen, B. Muller, S. Brockmoller, Tuulikki Seppänen-Laakso, J. Budczies, Elmar Bucher, Laxman Yetukuri, Sandra Castillo, Emilia Berg, Heli Nygren, Marko Sysi-Aho, J. L. Griffin, O. Fiehn, S. Loibl, C. Richter-Ehrenstein, C. Radke, Tuulia Hyötyläinen, Olli KallioniemiKristiina Iljin, Matej Oresic

Research output: Contribution to journalArticleScientificpeer-review

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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.
Original languageEnglish
Pages (from-to)3236-3245
Number of pages10
JournalCancer Research
Volume71
Issue number9
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

Fingerprint

Membrane Lipids
Lipid Metabolism
Breast Neoplasms
Lipids
Genes
Neoplasms
Proteins
Phospholipids
Breast
Stearoyl-CoA Desaturase
Acetyl-CoA Carboxylase
Fatty Acid Synthases
Palmitates
Gene Silencing
Sterols
Phosphatidylcholines
Liquid Chromatography
Computer Simulation
Mass Spectrometry
Thyroid Gland

Cite this

Hilvo, Mika ; Denkert, C. ; Lehtinen, Laura ; Muller, B. ; Brockmoller, S. ; Seppänen-Laakso, Tuulikki ; Budczies, J. ; Bucher, Elmar ; Yetukuri, Laxman ; Castillo, Sandra ; Berg, Emilia ; Nygren, Heli ; Sysi-Aho, Marko ; Griffin, J. L. ; Fiehn, O. ; Loibl, S. ; Richter-Ehrenstein, C. ; Radke, C. ; Hyötyläinen, Tuulia ; Kallioniemi, Olli ; Iljin, Kristiina ; Oresic, Matej. / Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression. In: Cancer Research. 2011 ; Vol. 71, No. 9. pp. 3236-3245.
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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.",
author = "Mika Hilvo and C. Denkert and Laura Lehtinen and B. Muller and S. Brockmoller and Tuulikki Sepp{\"a}nen-Laakso and J. Budczies and Elmar Bucher and Laxman Yetukuri and Sandra Castillo and Emilia Berg and Heli Nygren and Marko Sysi-Aho and Griffin, {J. L.} and O. Fiehn and S. Loibl and C. Richter-Ehrenstein and C. Radke and Tuulia Hy{\"o}tyl{\"a}inen and Olli Kallioniemi and Kristiina Iljin and Matej Oresic",
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Hilvo, M, Denkert, C, Lehtinen, L, Muller, B, Brockmoller, S, Seppänen-Laakso, T, Budczies, J, Bucher, E, Yetukuri, L, Castillo, S, Berg, E, Nygren, H, Sysi-Aho, M, Griffin, JL, Fiehn, O, Loibl, S, Richter-Ehrenstein, C, Radke, C, Hyötyläinen, T, Kallioniemi, O, Iljin, K & Oresic, M 2011, 'Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression', Cancer Research, vol. 71, no. 9, pp. 3236-3245. https://doi.org/10.1158/0008-5472.CAN-10-3894

Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression. / Hilvo, Mika; Denkert, C.; Lehtinen, Laura; Muller, B.; Brockmoller, S.; Seppänen-Laakso, Tuulikki; Budczies, J.; Bucher, Elmar; Yetukuri, Laxman; Castillo, Sandra; Berg, Emilia; Nygren, Heli; Sysi-Aho, Marko; Griffin, J. L.; Fiehn, O.; Loibl, S.; Richter-Ehrenstein, C.; Radke, C.; Hyötyläinen, Tuulia; Kallioniemi, Olli; Iljin, Kristiina; Oresic, Matej.

In: Cancer Research, Vol. 71, No. 9, 2011, p. 3236-3245.

Research output: Contribution to journalArticleScientificpeer-review

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

VL - 71

SP - 3236

EP - 3245

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 9

ER -