MESI-STRAT

Overview

MESI-STRAT: Systems Medicine of Metabolic-Signaling Networks -A New Concept for Breast Cancer Patient Stratification. Breast cancer is a complex disease with high prevalence in the European Union and world-wide. 75%-80 of the patients have estrogen receptor-positive (ER)-positive tumors and are treated with endocrine therapies. Endocrine therapies, which block ER-driven tumor growth, show high efficacy. Yet, a significant proportion of the patients will eventually relapse with metastatic breast cancer, and the recurrence rates remain almost constant for up to 20 years. MESI-STRAT develops metabolite marker panels measurable in biological fluids to enable patient stratification, resistance monitoring and clinical decision-making throughout endocrine therapy. This is a new concept as breast cancer metabolism is poorly explored for diagnostics and therapy. Upon successful validation in preclinical models, the predictive marker panels and related treatments will be jointly investigated by MESI-STRAT’s clinical and industrial partners. The MESI-STRAT consortium explores the interplay of breast cancer metabolism and oncogenic signaling (MEtabolic SIgnaling) by systems medicine approaches. MESI-STRAT develops new models for knowledge-based STRATification of patients into subgroups with different endocrine therapy resistance mechanisms.

Programme: This Project is not associated with a Programme

SEEK ID: https://fairdomhub.org/projects/99

Public web page: http://www.mesi-strat.eu

Organisms: Homo sapiens, Mus musculus, Rattus norvegicus

FAIRDOM PALs: No PALs for this Project

Project created: 26th Feb 2018

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Carmen Albertini

Projects: MESI-STRAT

Institutions: Medical University Innsbruck

Tobias Anzeneder

Projects: MESI-STRAT

Institutions: PATH - Patients' Tumor Bank of Hope

Barbara Bakker project_administrator

Projects: SilicoTryp, Multiscale modelling of state transitions in the host-microbiome-brain network, MESI-STRAT, PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Groningen

https://orcid.org/0000-0001-6274-3633
Cecilia Barile

Projects: MESI-STRAT

Institutions: University of Innsbruck

Regina Berger

Projects: MESI-STRAT

Institutions: Medical University Innsbruck

Peter Clark

Projects: MESI-STRAT

Institutions: University of Newcastle

Dyah Dewi : inactive since 2020-01-24

Projects: MESI-STRAT

Institutions: German Cancer Research Center (DKFZ)

Daniel Egle

Projects: MESI-STRAT

Institutions: Medical University Innsbruck

Jeroen Elassaiss-Schaap

Projects: MESI-STRAT

Institutions: PD-Value

Petra Engele

Projects: MESI-STRAT

Institutions: University of Innsbruck

Sabine Gack

Projects: MESI-STRAT

Institutions: University of Heidelberg

Cornelia Gieseler

Projects: MESI-STRAT

Institutions: Charité University Medicine Berlin

Franziska Goertler

Projects: MESI-STRAT

Institutions: University of Bergen

Sushma Nagaraja Grellscheid

Projects: Stress granules, MESI-STRAT

Institutions: University of Bergen

Alexander Heberle

Projects: MESI-STRAT

Institutions: University of Groningen

https://orcid.org/0000-0001-6414-8707
Ines Heiland project_administrator

Projects: MESI-STRAT, NAD COMPARTMENTATION, NAD phylogeny

Institutions: The Arctic University of Norway (UiT)

Karl-Heinz Kellner

Projects: MESI-STRAT

Institutions: Neuroimmun GmbH

Olga Krebs adminproject_administratorasset_housekeeperasset_gatekeeperprogramme_administrator

Projects: SysMO DB, FAIRDOM, ICYSB 2015 - International Practical Course in Systems Biology, ZucAt, SysMO-LAB, Kinetics on the move - Workshop 2016, Example use cases, FAIRDOM user meeting, ErasysApp Funders, EraCoBiotech 2 nd call proposal preparation, Service to URV Tarragona, Spain with respect to their Safety Assessment of Endocrine Disrupting Chemicals model (Active NOW), FAIRDOM & LiSyM & de.NBI Data Structuring Training, MESI-STRAT, INCOME, Multiscale modelling of state transitions in the host-microbiome-brain network, BESTER, TRALAMINOL, Sustainable co-production, INDIE - Biotechnological production of sustainable indole, Extremophiles metabolsim, PoLiMeR - Polymers in the Liver: Metabolism and Regulation, GB-XMap: Assessing the risk of gut-brain cross-diseases Investigating the gut-brain-axis, NAD COMPARTMENTATION, HOTSOLUTE, Stress granules, FAIRDOM Community Workers, GMDS Project Group "FAIRe Dateninfrastrukturen für die Biomedizinische Informatik", Mechanism based modeling viral disease ( COVID-19 ) dynamics in human population, COVID-19 Disease Map, AquaHealth (ERA-BlueBio), LiSyM Core Infrastructure and Management (LiSyM-PD), Early Metabolic Injury (LiSyM-EMI - Pillar I), Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III), Chronic Liver Disease Progression (LiSyM-DP - Pillar II), Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV), The Hedgehog Signalling Pathway (LiSyM-JGMMS), Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP), Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM), Modelling COVID-19 epidemics, SNAPPER: Synergistic Neurotoxicology APP for Environmental Regulation, SCyCode The Autotrophy-Heterotrophy Switch in Cyanobacteria: Coherent Decision-Making at Multiple Regulatory Layers, SASKit: Senescence-Associated Systems diagnostics Kit for cancer and stroke, CC-TOP, BioCreative VII

Institutions: Heidelberg Institute for Theoretical Studies (HITS gGmbH), FAIRDOM User meeting, Norwegian University of Science and Technology, University of Rostock

https://orcid.org/0000-0003-3540-0402
Anika Köck

Projects: MESI-STRAT

Institutions: Medical University Innsbruck

Miriam Langelaar

Projects: MESI-STRAT

Institutions: University Medical Centre Groningen

Charité University Medicine Berlin

Country:  Germany

City: Berlin

Web page: http://www.charite.de/

De Duve Institute

Country:  Belgium

City: Bruxelles

Web page: https://www.deduveinstitute.be

German Cancer Research Center (DKFZ)

Country:  Germany

City: Heidelberg

Web page: http://www.dkfz.de/en/index.html

Heidelberg Institute for Theoretical Studies (HITS gGmbH)

Country:  Germany

City: Heidelberg

Web page: http://www.h-its.org/

Medical University Innsbruck

Country:  Austria

City: Innsbruck

Web page: https://www.i-med.ac.at/universitaet/index.html.en

Neuroimmun GmbH

Country:  Germany

City: Karlsruhe

Web page: https://www.neuroimmun.com/

PATH - Patients' Tumor Bank of Hope

Country:  Germany

City: München

Web page: http://path-biobank.org/index.php/de/

PD-Value

Country:  Netherlands

City: Leiden

Web page: http://pd-value.biz/

SysBioSim

Country:  Netherlands

City: Leiden

Web page: http://sysbiosim.com/

The Arctic University of Norway (UiT)

Country:  Norway

City: Tromsø

Web page: https://en.uit.no/startsida

University Medical Centre Groningen

Country:  Netherlands

City: Not specified

Web page: Not specified

University of Bergen

Country:  Norway

City: Not specified

Web page: Not specified

University of Groningen

Country:  Netherlands

City: Groningen

Web page: http://www.rug.nl/corporate/index

University of Heidelberg

Country:  Germany

City: Heidelberg

Web page: http://www.uni-heidelberg.de/index_e.html

University of Innsbruck

Country:  Austria

City: Innsbruck

Web page: https://www.uibk.ac.at/

University of Newcastle

Country:  United Kingdom

City: Newcastle

Web page: http://www.ncl.ac.uk/camb/

Vall d´Hebron Institute of Oncology (VHIO)

Country:  Spain

City: Barcelona

Web page: http://www.vhio.net/en

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MCF-7
MESI-STRAT

Submitter: Pamela Riemer

Provider Name: Opitz lab

Provider's strain ID: MCF-7

Organism: Homo sapiens

Genotypes: wild-type

Phenotypes: wild-type

Comment: The cells were sent to CHAB from Opitz lab and STR profiled to confirm their identity. Their mutational pattern was analysed by panel DNA sequencing as described in file "MESI-STRATcells.docx".

MESI-STRAT Newsletter June 2019
MESI-STRAT

First MESI-STRAT Newsletter June 2019

Creators: Petra Engele, Kathrin Thedieck, Tobias Anzeneder, Janina Leyk

Submitter: Petra Engele

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Human genomic DNA extraction
MESI-STRAT

Standard Operating Procedure for human genomic DNA extraction ( copied from GEO DataSets GSM1375121)

Creators: Olga Krebs, Christiane Opitz

Submitter: Olga Krebs

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IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression
MESI-STRAT

Abstract (Expand)

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded … systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.

Authors: Ahmed Sadik, Luis F. Somarribas Patterson, Selcen Öztürk, Soumya R. Mohapatra, Verena Panitz, Philipp F. Secker, Pauline Pfänder, Stefanie Loth, Heba Salem, Mirja Tamara Prentzell, Bianca Berdel, Murat Iskar, Erik Faessler, Friederike Reuter, Isabelle Kirst, Verena Kalter, Kathrin I. Foerster, Evelyn Jäger, Carina Ramallo Guevara, Mansour Sobeh, Thomas Hielscher, Gernot Poschet, Annekathrin Reinhardt, Jessica C. Hassel, Marc Zapatka, Udo Hahn, Andreas von Deimling, Carsten Hopf, Rita Schlichting, Beate I. Escher, Jürgen Burhenne, Walter E. Haefeli, Naveed Ishaque, Alexander Böhme, Sascha Schäuble, Kathrin Thedieck, Saskia Trump, Martina Seiffert, Christiane A. Opitz

Date Published: 1st Sep 2020

Publication Type: Journal

Breaking the Interface: Efficient Extraction of Magnetic Beads from Nanoliter Droplets for Automated Sequential Immunoassays
MESI-STRAT

Abstract (Expand)

Droplet-based microfluidic systems offer a high potential for miniaturization and automation. Therefore, they are becoming an increasingly important tool in analytical chemistry, biosciences, and … medicine. Heterogeneous assays commonly utilize magnetic beads as a solid phase. However, the sensitivity of state of the art microfluidic systems is limited by the high bead concentrations required for efficient extraction across the water–oil interface. Furthermore, current systems suffer from a lack of technical solutions for sequential measurements of multiple samples, limiting their throughput and capacity for automation. Taking advantage of the different wetting properties of hydrophilic and hydrophobic areas in the channels, we improve the extraction efficiency of magnetic beads from aqueous nanoliter-sized droplets by 2 orders of magnitude to the low μg/mL range. Furthermore, the introduction of a switchable magnetic trap enables repetitive capture and release of magnetic particles for sequential analysis of multiple samples, enhancing the throughput. In comparison to conventional ELISA-based sandwich immunoassays on microtiter plates, our microfluidic setup offers a 25–50-fold reduction of sample and reagent consumption with up to 50 technical replicates per sample. The enhanced sensitivity and throughput of this system open avenues for the development of automated detection of biomolecules at the nanoliter scale.

Authors: Lukas Metzler, Ulrike Rehbein, Jan-Niklas Schönberg, Thomas Brandstetter, Kathrin Thedieck, Jürgen Rühe

Date Published: 4th Aug 2020

Publication Type: Journal

The therapeutic potential of targeting tryptophan catabolism in cancer.
MESI-STRAT

Abstract (Expand)

Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. … Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

Authors: C. A. Opitz, L. F. Somarribas Patterson, S. R. Mohapatra, D. L. Dewi, A. Sadik, M. Platten, S. Trump

Date Published: 11th Dec 2019

Publication Type: Journal

Resistance Exercise Reduces Kynurenine Pathway Metabolites in Breast Cancer Patients Undergoing Radiotherapy
MESI-STRAT

Abstract (Expand)

Purpose: Evidence from preclinical studies and trials in healthy volunteers suggests that exercise may modulate the levels of tryptophan (TRP) metabolites along the kynurenine (KYN) pathway. As KYN and … downstream KYN metabolites are known to promote cancer progression by inhibiting anti-tumor immune responses and by promoting the motility of cancer cells, we investigated if resistance exercise can also control the levels of KYN pathway metabolites in breast cancer patients undergoing radiotherapy (NCT01468766). Patients and Methods: Chemotherapy-naïve breast cancer patients (n = 96) were either randomized to an exercise/intervention group (IG) or a control group (CG). The IG participated in a 12-week supervised progressive resistance exercise program twice a week, whereas the CG received a supervised relaxation program. Serum levels of TRP and KYN as well as urine levels of kynurenic acid (KYNA) and neurotoxic quinolinic acid (QUINA) were assessed before (t0), after radiotherapy, and mid-term of the exercise intervention (t1) and after the exercise intervention (t2). Additionally, 24 healthy women (HIG) participated in the exercise program to investigate potential differences in its effects on KYN metabolites in comparison to the breast cancer patients. Results: At baseline (t0) the breast cancer patients showed a significantly elevated serum KYN/TRP ratio and urine QUINA/KYNA ratio, as well as increased urine QUINA levels in comparison to the healthy women. In response to exercise the healthy women and the breast cancer patients differed significantly in the levels of urine QUINA and the QUINA/KYNA ratio. Most importantly, serum KYN levels and the KYN/TRP ratio were significantly reduced in exercising patients (IG) compared to non-exercising patients (CG) both at t1 and t2. Conclusion: Resistance exercise may represent a potent non-pharmacological avenue to counteract an activation of the KYN pathway in breast cancer patients undergoing radiotherapy.

Authors: Philipp Zimmer, Martina E. Schmidt, Mirja Tamara Prentzell, Bianca Berdel, Joachim Wiskemann, Karl Heinz Kellner, Jürgen Debus, Cornelia Ulrich, Christiane A. Opitz, Karen Steindorf

Date Published: 25th Sep 2019

Publication Type: Not specified

Identification of evolutionary and kinetic drivers of NAD-dependent signaling.
MESI-STRAT

Abstract (Expand)

Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. … NAD-dependent signaling (e.g., by sirtuins and poly-adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.

Authors: M. Bockwoldt, D. Houry, M. Niere, T. I. Gossmann, I. Reinartz, A. Schug, M. Ziegler, I. Heiland

Date Published: 6th Aug 2019

Publication Type: Journal

Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond
MESI-STRAT

Abstract (Expand)

L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders … ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases. Full text of this paper is available here https://inrepo01.inet.dkfz-heidelberg.de/record/143705

Authors: Michael Platten, Ellen A. A. Nollen, Ute F. Röhrig, Francesca Fallarino, Christiane A. Opitz

Date Published: 1st May 2019

Publication Type: Journal

The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner
MESI-STRAT

Abstract (Expand)

All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under … stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translationinhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stressgranule- kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly.When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new prosurvival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.

Authors: Alexander Martin Heberle, Patricia Razquin Navas, Miriam Langelaar-Makkinje, Katharina Kasack, Ahmed Sadik, Erik Faessler, Udo Hahn, Philip Marx-Stoelting, Christiane A Opitz, Christine Sers, Ines Heiland, Sascha Schäuble, Kathrin Thedieck

Date Published: 28th Mar 2019

Publication Type: Not specified

Copy number profiling by array comparative genomic hybridization identifies frequently occurring BRCA2-like male breast cancer.
MESI-STRAT

Abstract (Expand)

Genomic aberrations can be used to subtype breast cancer. In this study, we investigated DNA copy number (CN) profiles of 69 cases of male breast cancer (MBC) by array comparative genomic hybridization … (aCGH) to detect recurrent gains and losses in comparison with female breast cancers (FBC). Further, we classified these profiles as BRCA1-like, BRCA2-like or non-BRCA-like profiles using previous classifiers derived from FBC, and correlated these profiles with pathological characteristics. We observed large CN gains on chromosome arms 1q, 5p, 8q, 10p, 16p, 17q, and chromosomes 20 and X. Large losses were seen on chromosomes/chromosome arms 1p, 6p, 8p, 9, 11q, 13, 14q, 16q, 17p, and 22. The pattern of gains and losses in estrogen receptor positive (ER+) MBC was largely similar to ER+ FBC, except for gains on chromosome X in MBC, which were uncommon in FBC. Out of 69 MBC patients, 15 patients (22%) had a BRCA2-like profile, of which 2 (3%) were also BRCA1-like. One patient (1%) was only BRCA1-like; the remaining 53 (77%) patients were classified as non-BRCA-like. BRCA2-like cases were more often p53 accumulated than non-BRCA-like cases (P = 0.014). In conclusion, the pattern of gains and losses in ER+ MBC was largely similar to that of its ER+ FBC counterpart, except for gains on chromosome X in MBC, which are uncommon in FBC. A significant proportion of MBC has a BRCA2-like aCGH profile, pointing to a potentially hereditary nature, and indicating that they could benefit from a drug regimen targeting BRCA defects as in FBC.

Authors: H. D. Biesma, P. C. Schouten, M. M. Lacle, J. Sanders, W. Brugman, R. Kerkhoven, I. Mandjes, P. van der Groep, P. J. van Diest, S. C. Linn

Date Published: 11th Sep 2015

Publication Type: Journal

Model of tryptophan metabolism, readily scalable using tissue-specific gene expression data.
MESI-STRAT

Abstract (Expand)

Tryptophan is utilized in various metabolic routes including protein synthesis, serotonin, and melatonin synthesis and the kynurenine pathway. Perturbations in these pathways have been associated with … neurodegenerative diseases and cancer. Here we present a comprehensive kinetic model of the complex network of human tryptophan metabolism based upon existing kinetic data for all enzymatic conversions and transporters. By integrating tissue-specific expression data, modeling tryptophan metabolism in liver and brain returned intermediate metabolite concentrations in the physiological range. Sensitivity and metabolic control analyses identified expected key enzymes to govern fluxes in the branches of the network. Combining tissue-specific models revealed a considerable impact of the kynurenine pathway in liver on the concentrations of neuroactive derivatives in the brain. Moreover, using expression data from a cancer study predicted metabolite changes that resembled the experimental observations. We conclude that the combination of the kinetic model with expression data represents a powerful diagnostic tool to predict alterations in tryptophan metabolism. The model is readily scalable to include more tissues, thereby enabling assessment of organismal tryptophan metabolism in health and disease.

Authors: A. K. Stavrum, I. Heiland, S. Schuster, P. Puntervoll, M. Ziegler

Date Published: 29th Nov 2013

Publication Type: Journal

Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker.
MESI-STRAT

Abstract (Expand)

INTRODUCTION: Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive … subgroups, and to compare them with female breast cancer (FBC). METHODS: A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs. RESULTS: Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC. CONCLUSIONS: We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.

Authors: I. Johansson, C. Nilsson, P. Berglund, M. Lauss, M. Ringner, H. Olsson, L. Luts, E. Sim, S. Thorstensson, M. L. Fjallskog, I. Hedenfalk

Date Published: 14th Feb 2012

Publication Type: Journal

Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer.
MESI-STRAT

Abstract (Expand)

Kynurenine formation by tryptophan-catabolic indoleamine-2,3-dioxygenase 1 (IDO1) plays a key role in tumor immune evasion and inhibition of IDO1 is efficacious in preclinical models of breast cancer. … As the response of breast cancer to immune checkpoint inhibitors may be limited, a better understanding of the expression of additional targetable immunomodulatory pathways is of importance. We therefore investigated the regulation of IDO1 expression in different breast cancer subtypes. We identified estrogen receptor alpha (ER) as a negative regulator of IDO1 expression. Serum kynurenine levels as well as tumoral IDO1 expression were lower in patients with ER-positive than ER-negative tumors and an inverse relationship between IDO1 and estrogen receptor mRNA was observed across 14 breast cancer data sets. Analysis of whole genome bisulfite sequencing, 450k, MassARRAY and pyrosequencing data revealed that the IDO1 promoter is hypermethylated in ER-positive compared with ER-negative breast cancer. Reduced induction of IDO1 was also observed in human ER-positive breast cancer cell lines. IDO1 induction was enhanced upon DNA demethylation in ER-positive but not in ER-negative cells and methylation of an IDO1 promoter construct reduced IDO1 expression, suggesting that enhanced methylation of the IDO1 promoter suppresses IDO1 in ER-positive breast cancer. The association of ER overexpression with epigenetic downregulation of IDO1 appears to be a particular feature of breast cancer as IDO1 was not suppressed by IDO1 promoter hypermethylation in the presence of high ER expression in cervical or endometrial cancer.

Authors: D. L. Dewi, S. R. Mohapatra, S. Blanco Cabanes, I. Adam, L. F. Somarribas Patterson, B. Berdel, M. Kahloon, L. Thurmann, S. Loth, K. Heilmann, D. Weichenhan, O. Mucke, I. Heiland, P. Wimberger, J. D. Kuhlmann, K. H. Kellner, S. Schott, C. Plass, M. Platten, C. Gerhauser, S. Trump, C. A. Opitz

Date Published: No date defined

Publication Type: Not specified

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MESI-STRAT Newsletter June 2021
MESI-STRAT

Project News June 2021

Creators: Petra Engele, Anika Köck, Mirja Tamara Prentzell

Submitter: Petra Engele

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MESI-STRAT Newsletter Juni 2021 deutsch
MESI-STRAT

Neues vom MESI-STRAT Projekt Juni 2021

Creators: Petra Engele, Anika Köck, Mirja Tamara Prentzell

Submitter: Petra Engele

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MESI-STRAT Newsletter Juni 2020 (deutsch)
MESI-STRAT

In unserem MESI-STRAT Newsletter erfahren Sie Neuigkeiten über unser Konsortium und unsere Forschung

Creators: Petra Engele, Marta Palafox

Submitter: Petra Engele

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MESI-STRAT Newsletter June 2020 (english)
MESI-STRAT

In our newsletter you will learn all about our consortium and the progress of our research.

Creators: Petra Engele, Marta Palafox

Submitter: Petra Engele

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MESI-STRAT Newsletter Dezember 2020 (deutsch)
MESI-STRAT

Newsletter mit Neuigkeiten aus unserem Projekt

Creators: Petra Engele, Alexander Heberle, Christiane Opitz, Daryl Shanley

Submitter: Petra Engele

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MESI-STRAT Newsletter December 2020 (english)
MESI-STRAT

News of our project

Creators: Petra Engele, Alexander Heberle, Christiane Opitz, Daryl Shanley

Submitter: Petra Engele

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MESI-STRAT General Information Flyer (english)
MESI-STRAT
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Creator: Petra Engele

Submitter: Petra Engele

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MESI-STRAT General Information Flyer (german)
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MESI-STRAT Newsletter Oktober 2019 deutsch
MESI-STRAT

Newsletter Oktober 2019 deutsche Fassung

Creators: Petra Engele, Tobias Anzeneder, Suraj Sharma

Submitter: Petra Engele

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MESI-STRAT Newsletter October 2019
MESI-STRAT

Newsletter October 2019

Creators: Petra Engele, Tobias Anzeneder, Suraj Sharma

Submitter: Petra Engele

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