Summary of Study ST001984

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001260. The data can be accessed directly via it's Project DOI: 10.21228/M8V401 This work is supported by NIH grant, U2C- DK119886.

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Study IDST001984
Study TitleMetabolic adaptations in an endocrine-related breast cancer mouse model unveil potential markers of tumor response to hormonal therapy
Study Typecase - control study
Study SummaryBreast cancer (BC) is the most common type of cancer in women and, in most cases, it is hormone-dependent (HD), thus relying on ovarian hormone activation of intracellular receptors to stimulate tumor growth. Endocrine therapy (ET) aimed at preventing hormone receptor activation is the primary treatment strategy, however, about half of the patients, develop resistance in time. This involves the development of hormone independent tumors that initially are ET-responsive (HI), which may subsequently become resistant (HIR). The mechanisms that promote the conversion of HI to HIR tumors are varied and not completely understood. The aim of this work was to characterize the metabolic adaptations accompanying this conversion through the analysis of the polar metabolomes of tumor tissue and non-compromised mammary gland from mice implanted subcutaneously with HD, HI and HIR tumors from a medroxyprogesterone acetate (MPA)-induced BC mouse model. This was carried out by nuclear magnetic resonance (NMR) spectroscopy of tissue polar extracts and data mining through multivariate and univariate statistical analysis. Initial results unveiled marked changes between global tumor profiles and non-compromised mammary gland tissues, as expected. More importantly, specific metabolic signatures were found to accompany progression from HD, through HI and to HIR tumors, impacting on amino acids, nucleotides, membrane percursors and metabolites related to oxidative stress protection mechanisms. For each transition, sets of polar metabolites are advanced as potential markers of progression, including acquisition of resistance to ET. Putative biochemical interpretation of such signatures are proposed and discussed.
Institute
University of Aveiro
DepartmentChemistry
LaboratoryMetabolomics
Last NameSilva
First NameAna
AddressCampus Universitário de Santiago, 3810-193
Emailanarita.asilva@ua.pt
Phone234370200
Submit Date2021-10-06
Num Groups8
Total Subjects48
Num Females48
Study CommentsFor this study 48 female 2-month old Balb/c mice were used
Analysis Type DetailNMR
Release Date2021-12-01
Release Version1
Ana Silva Ana Silva
https://dx.doi.org/10.21228/M8V401
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001260
Project DOI:doi: 10.21228/M8V401
Project Title:Metabolic adaptations in an endocrine-related breast cancer mouse model unveil potential markers of tumor response to hormonal therapy
Project Type:NMR spectra
Project Summary:Breast cancer (BC) is the most common type of cancer in women and, in most cases, it is hormone-dependent (HD), thus relying on ovarian hormone activation of intracellular receptors to stimulate tumor growth. Endocrine therapy (ET) aimed at preventing hormone receptor activation is the primary treatment strategy, however, about half of the patients, develop resistance in time. This involves the development of hormone independent tumors that initially are ET-responsive (HI), which may subsequently become resistant (HIR). The mechanisms that promote the conversion of HI to HIR tumors are varied and not completely understood. The aim of this work was to characterize the metabolic adaptations accompanying this conversion through the analysis of the polar metabolomes of tumor tissue and non-compromised mammary gland from mice implanted subcutaneously with HD, HI and HIR tumors from a medroxyprogesterone acetate (MPA)-induced BC mouse model. This was carried out by nuclear magnetic resonance (NMR) spectroscopy of tissue polar extracts and data mining through multivariate and univariate statistical analysis. Initial results unveiled marked changes between global tumor profiles and non-compromised mammary gland tissues, as expected. More importantly, specific metabolic signatures were found to accompany progression from HD, through HI and to HIR tumors, impacting on amino acids, nucleotides, membrane percursors and metabolites related to oxidative stress protection mechanisms. For each transition, sets of polar metabolites are advanced as potential markers of progression, including acquisition of resistance to ET. Putative biochemical interpretation of such signatures are proposed and discussed.
Institute:University of Aveiro
Department:Chemistry
Laboratory:Metabolomics
Last Name:Araújo
First Name:Rita
Address:Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
Email:anarita.asilva@ua.pt
Phone:913355325
Funding Source:This work was developed within the scope of the project CICECO Aveiro Institute of Materials, UIDB/50011/2020 and UIDP/50011/2020, financed by national funds through the FCT/MCTE and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. AMG acknowledges the Portuguese National NMR Network (RNRMN), supported by FCT funds, and RA thanks RNRMN for her grant through the Doctoral Program in NMR applied to Chemistry, Materials and Biosciences – PTNMRPhD (PD/00065/2013). The authors also acknowledge financial support from the Portuguese Foundation for Science and Technology through projects UIDB/04501/2020, UIDP/04501/2020, MEDISIS (CENTRO-01-0246-FEDER-000018) and pAGE (CENTRO-01-0145-FEDER-000003) project cofounded through the Comissão de Coordenação e Desenvolvimento Regional do Centro and COMPETE 2020 program and European Union fund FEDER (L.H.). The authors also acknowledge the Agencia Nacional de Promoción Científica y Tecnológica, Argentina (ANPCYT); grant PICT 2017-2073 (C.L.).

Subject:

Subject ID:SU002065
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Genotype Strain:Balb/c
Age Or Age Range:2 month-old
Gender:Female
Animal Animal Supplier:Animal Facility at the Instituto de Biología y Medicina Experimental (IByME) of Buenos Aires, in Argentina.
Animal Housing:Animal Facility at the Instituto de Biología y Medicina Experimental (IByME) of Buenos Aires, in Argentina.
Animal Light Cycle:12 h light/dark cycle
Animal Feed:fed ad libitum
Animal Water:fed ad libitum

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample type
SA185699B71control
SA185700B77control
SA185701B65control
SA185702B53control
SA185703B47control
SA185704C11control
SA185705B59control
SA185706C17control
SA185707C41control
SA185708A17control
SA185709C35control
SA185710C29control
SA185711C23control
SA185712B41control
SA185713B83control
SA185714A41control
SA185715A53control
SA185716A59control
SA185717A34control
SA185718A29control
SA185719A23control
SA185720B35control
SA185721A65control
SA185722A47control
SA185723B17control
SA185724B29control
SA185725A83control
SA185726B23control
SA185727A77control
SA185728A71control
SA185729C43tumor
SA185730C44tumor
SA185731C45tumor
SA185732B99tumor
SA185733B98tumor
SA185734B97tumor
SA185735C46tumor
SA185736B108tumor
SA185737C54tumor
SA185738C52tumor
SA185739C53tumor
SA185740B107tumor
SA185741C51tumor
SA185742C50tumor
SA185743C48tumor
SA185744C49tumor
SA185745C47tumor
SA185746B88tumor
SA185747B91tumor
SA185748B92tumor
SA185749B93tumor
SA185750B90tumor
SA185751B89tumor
SA185752B85tumor
SA185753B86tumor
SA185754B87tumor
SA185755B94tumor
SA185756B95tumor
SA185757B103tumor
SA185758B104tumor
SA185759B105tumor
SA185760B102tumor
SA185761B101tumor
SA185762B96tumor
SA185763B100tumor
SA185764B106tumor
Showing results 1 to 66 of 66

Collection:

Collection ID:CO002058
Collection Summary:Tumor samples and axial mammary gland (MG) tissue from the same animal were excised and immediately frozen in liquid nitrogen. In parallel, a group of mice (n=6) without tumors were grown in identical conditions (+/- 20 mg MPA depot), to obtain healthy MG tissue for comparison
Sample Type:Breast

Treatment:

Treatment ID:TR002077
Treatment Summary:Briefly, the parental tumor line, C4-HD, was induced by treatment of BALB/c female mouse with MPA depot and always transplanted with MPA to sustain growth (hormone-dependent; HD growth).

Sample Preparation:

Sampleprep ID:SP002071
Sampleprep Summary:Both tumor and MG tissue were ground using a pestle and mortar, while kept in liquid nitrogen. All tissue samples (average weight of 50 mg) were extracted using methanol: chloroform: water (1:1:0.75) and the polar phase was separated for analysis. In brief, ground tissue samples were transferred to an eppendorf tube, followed by the addition of 500 µL of cold 80% methanol, 400µL of cold chloroform and 200 µL of cold Mili-Q water, and vortex homogenisation for 60 s. Samples were left to rest on ice for 10 minutes and then centrifuged (8,000 rpm, 5 min, 23 ºC). Polar phases were separated, vacuum-dried and stored at -80ºC until analysis. At the time of NMR acquisition, the dried aqueous extracts were suspended in 600 µL of 100 mM sodium phosphate buffer (pH 7.4, in D2O containing 0.25% 3-(trimethylsilyl)-propionic-2,2,3,3-d4 acid (TSP) for chemical shift referencing), homogenized, and 550 µL were transferred to 5mm NMR tubes. All NMR spectra were acquired on a Bruker AVANCE III spectrometer (Rheinstetten, Germany) operating at 500.13 MHz for proton. Standard 1D 1H NMR spectra of aqueous extracts were recorded at 298 K with water presaturation, using the “noesypr1d” pulse program (Bruker library), with 2.34 s acquisition time, 2 s relaxation delay, 512 scans, 7002.801 Hz spectral width, and 32 k data points. Each free-induction decay was zero-filled to 64 k points and multiplied by a 0.3 Hz exponential function prior to Fourier transformation. After acquisition, spectra were manually phased, baseline-corrected, and chemical-shift referenced to TSP. For selected samples, two-dimensional NMR spectra, namely 1H-1H TOCSY (Total Correlation Spectroscopy) and 1H-13C HSQC (Heteronuclear Single Quantum Coherence) spectra were also recorded to support spectral assignment. Peak assignment was also based on comparison with data available on the Bruker BBIOREFCODE spectral database and the human metabolome database (HMDB), as well as on existing literature.

Analysis:

Analysis ID:AN003235
Analysis Type:NMR
Num Factors:2
Num Metabolites:37
Units:ua

NMR:

NMR ID:NM000223
Analysis ID:AN003235
Instrument Name:Spectrometer BRUKER AVANCE III TM HD 500 MHz
Instrument Type:Other
NMR Experiment Type:1D-1H
Spectrometer Frequency:500 MHz
NMR Solvent:D2O
NMR Tube Size:5mm
Shimming Method:manual
Receiver Gain:203
Temperature:298º K
Number Of Scans:512
Dummy Scans:8
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