| 1. |
- Brockmöller, Scarlet F., et al.
(författare)
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Integration of metabolomics and expression of glycerol-3-phosphate acyltransferase (GPAM) in breast cancer-link to patient survival, hormone receptor status, and metabolic profiling
- 2012
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 11:2, s. 850-60
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Tidskriftsartikel (refereegranskat)abstract
- Changes in lipid metabolism are an important but not well-characterized hallmark of cancer. On the basis of our recent findings of lipidomic changes in breast cancer, we investigated glycerol-3-phosphate acyltransferase (GPAM), a key enzyme in the lipid biosynthesis of triacylglycerols and phospholipids. GPAM protein expression was evaluated and linked to metabolomic and lipidomic profiles in a cohort of human breast carcinomas. In addition, GPAM mRNA expression was analyzed using the GeneSapiens in silico transcriptiomics database. High cytoplasmic GPAM expression was associated with hormone receptor negative status (p = 0.013). On the protein (p = 0.048) and mRNA (p = 0.001) levels, increased GPAM expression was associated with a better overall survival. Metabolomic analysis by GC-MS showed that sn-glycerol-3-phosphate, the substrate of GPAM, was elevated in breast cancer compared to normal breast tissue. LC-MS based lipidomic analysis identified significantly higher levels of phospholipids, especially phosphatidylcholines in GPAM protein positive tumors. In conclusion, our results suggest that GPAM is expressed in human breast cancer with associated changes in the cellular metabolism, in particular an increased synthesis of phospholipids, the major structural component of cellular membranes.
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| 2. |
- Budczies, Jan, et al.
(författare)
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Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer : alterations in glutamine and beta-alanine metabolism
- 2013
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Ingår i: Journal of Proteomics. - : Lippincott Williams & Wilkins. - 1874-3919 .- 1876-7737. ; 94, s. 279-288
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER-) breast cancer tissues were investigated using GC-TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER- subtype. Beta-alanine demonstrated the strongest change between ER- and ER+ breast cancer (fold change=2.4, p=1.5E-20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R=-0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER- breast cancer. In a Kaplan-Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR=0.6, p=3.2E-15).BIOLOGICAL SIGNIFICANCE: It is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER- breast as different diseases requiring different treatment strategies. Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER- breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER- subtype as a preferential target for glutaminase inhibitors. For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER- breast cancer.
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| 3. |
- Budczies, Jan, et al.
(författare)
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Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue - a GC-TOFMS based metabolomics study
- 2012
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Changes in energy metabolism of the cells are common to many kinds of tumors and are considered a hallmark of cancer. Gas chromatography followed by time-of-flight mass spectrometry (GC-TOFMS) is a well-suited technique to investigate the small molecules in the central metabolic pathways. However, the metabolic changes between invasive carcinoma and normal breast tissues were not investigated in a large cohort of breast cancer samples so far.RESULTS: A cohort of 271 breast cancer and 98 normal tissue samples was investigated using GC-TOFMS-based metabolomics. A total number of 468 metabolite peaks could be detected; out of these 368 (79%) were significantly changed between cancer and normal tissues (p<0.05 in training and validation set). Furthermore, 13 tumor and 7 normal tissue markers were identified that separated cancer from normal tissues with a sensitivity and a specificity of >80%. Two-metabolite classifiers, constructed as ratios of the tumor and normal tissues markers, separated cancer from normal tissues with high sensitivity and specificity. Specifically, the cytidine-5-monophosphate / pentadecanoic acid metabolic ratio was the most significant discriminator between cancer and normal tissues and allowed detection of cancer with a sensitivity of 94.8% and a specificity of 93.9%.CONCLUSIONS: For the first time, a comprehensive metabolic map of breast cancer was constructed by GC-TOF analysis of a large cohort of breast cancer and normal tissues. Furthermore, our results demonstrate that spectrometry-based approaches have the potential to contribute to the analysis of biopsies or clinical tissue samples complementary to histopathology.
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| 4. |
- Denkert, Carsten, et al.
(författare)
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Metabolomics of human breast cancer : new approaches for tumor typing and biomarker discovery
- 2012
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Ingår i: Genome Medicine. - London, United Kingdom : BioMed Central (BMC). - 1756-994X .- 1756-994X. ; 4:4
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Forskningsöversikt (refereegranskat)abstract
- Breast cancer is the most common cancer in women worldwide, and the development of new technologies for better understanding of the molecular changes involved in breast cancer progression is essential. Metabolic changes precede overt phenotypic changes, because cellular regulation ultimately affects the use of small-molecule substrates for cell division, growth or environmental changes such as hypoxia. Differences in metabolism between normal cells and cancer cells have been identified. Because small alterations in enzyme concentrations or activities can cause large changes in overall metabolite levels, the metabolome can be regarded as the amplified output of a biological system. The metabolome coverage in human breast cancer tissues can be maximized by combining different technologies for metabolic profiling. Researchers are investigating alterations in the steady state concentrations of metabolites that reflect amplified changes in genetic control of metabolism. Metabolomic results can be used to classify breast cancer on the basis of tumor biology, to identify new prognostic and predictive markers and to discover new targets for future therapeutic interventions. Here, we examine recent results, including those from the European FP7 project METAcancer consortium, that show that integrated metabolomic analyses can provide information on the stage, subtype and grade of breast tumors and give mechanistic insights. We predict an intensified use of metabolomic screens in clinical and preclinical studies focusing on the onset and progression of tumor development.
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| 5. |
- Gonzalez-Ericsson, Paula, et al.
(författare)
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The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers into breast cancer clinical trials and daily practice
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 250:5, s. 667-684
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
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| 6. |
- Hilvo, Mika, et al.
(författare)
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Monounsaturated fatty acids in serum triacylglycerols are associated with response to neoadjuvant chemotherapy in breast cancer patients
- 2014
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 134:7, s. 1725-1733
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Tidskriftsartikel (refereegranskat)abstract
- Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.
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| 7. |
- Hilvo, Mika, et al.
(författare)
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Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression
- 2011
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Ingår i: Cancer Research. - Philadelphia, PA, USA : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 71:9, s. 3236-45
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
- Hudeček, Jan, et al.
(författare)
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Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials
- 2020
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 6:1
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Forskningsöversikt (refereegranskat)abstract
- Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
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| 9. |
- Jerby, Livnat, et al.
(författare)
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Metabolic associations of reduced proliferation and oxidative stress in advanced breast cancer
- 2012
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 72:22, s. 5712-5720
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant metabolism is a hallmark of cancer, but whole metabolomic flux measurements remain scarce. To bridge this gap, we developed a novel metabolic phenotypic analysis (MPA) method that infers metabolic phenotypes based on the integration of transcriptomics or proteomics data within a human genome-scale metabolic model. MPA was applied to conduct the first genome-scale study of breast cancer metabolism based on the gene expression of a large cohort of clinical samples. The modeling correctly predicted cell lines' growth rates, tumor lipid levels, and amino acid biomarkers, outperforming extant metabolic modeling methods. Experimental validation was obtained in vitro. The analysis revealed a subtype-independent "go or grow" dichotomy in breast cancer, where proliferation rates decrease as tumors evolve metastatic capability. MPA also identified a stoichiometric tradeoff that links the observed reduction in proliferation rates to the growing need to detoxify reactive oxygen species. Finally, a fundamental stoichiometric tradeoff between serine and glutamine metabolism was found, presenting a novel hallmark of estrogen receptor (ER)(+) versus ER(-) tumor metabolism. Together, our findings greatly extend insights into core metabolic aberrations and their impact in breast cancer.
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| 10. |
- Kaidar-Person, Orit, et al.
(författare)
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The Lucerne Toolbox 2 to optimise axillary management for early breast cancer : a multidisciplinary expert consensus
- 2023
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Ingår i: EClinicalMedicine. - 2589-5370. ; 61
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Forskningsöversikt (refereegranskat)abstract
- Clinical axillary lymph node management in early breast cancer has evolved from being merely an aspect of surgical management and now includes the entire multidisciplinary team. The second edition of the “Lucerne Toolbox”, a multidisciplinary consortium of European cancer societies and patient representatives, addresses the challenges of clinical axillary lymph node management, from diagnosis to local therapy of the axilla. Five working packages were developed, following the patients’ journey and addressing specific clinical scenarios. Panellists voted on 72 statements, reaching consensus (agreement of 75% or more) in 52.8%, majority (51%–74% agreement) in 43.1%, and no decision in 4.2%. Based on the votes, targeted imaging and standardized pathology of lymph nodes should be a prerequisite to planning local and systemic therapy, axillary lymph node dissection can be replaced by sentinel lymph node biopsy ( ± targeted approaches) in a majority of scenarios; and positive patient outcomes should be driven by both low recurrence risks and low rates of lymphoedema.
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