PXD000281

PXD000281 is an original dataset announced via ProteomeXchange.

Title	Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer
Description	About one-third of oestrogen receptor alpha- positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen. Peptide and protein identification data set 1: Peptide identification from the MALDI-TOF/TOF data was carried out using the Paragon algorithm in the ProteinPilot 2.0 software package (Applied Biosystems) 46. Default settings for a 4800 instrument were used (i.e., no manual settings for mass tolerance was given). The following parameters were selected in the analysis method: iTRAQ 4plex peptide labelled as sample type, MMTS as alkylating agent of cysteine, trypsin as digesting enzyme, 4800 as instrument, gel based ID and Urea denaturation as special factors, biological modifications as ID focus, and thorough ID as search effort. Peptide identification from the Q-TOF data was carried out using the Spectrum Mill Protein Identification software (Agilent). Data was extracted between MH+ 600 and 4000 Da (Agilent's definition). Scans with the same precursor m/z 90 sec, 0.05 m/z matching with a minimum of 20 peaks in MS2 were merged. Peptide and protein identification data set 2: Proteome discoverer 1.3 with sequest-percolator was used for protein identification. Precursor mass tolerance was set to 10 ppm and for fragments 0.8 Da and 0.02 Da were used for detection in the linear iontrap and the orbitrap, respectively. Oxidized methionine and phosphorylation on S,T and Y was set as dynamic modifications, and carbamidomethylation, N-terminal 8plex iTRAQ, and lysyl 8plex iTRAQ as fixed modifications. Spectra were matched to ensembl 68 limited to human protein sequences, and results were filtered to 1% FDR.
HostingRepository	PRIDE
AnnounceDate	2013-07-24
AnnouncementXML	Submission_2013-07-24_07:32:35.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Henrik J Johansson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iTRAQ4plex-116 reporter+balance reagent acylated residue; iTRAQ8plex-116 reporter+balance reagent acylated residue; iodoacetamide derivatized residue; methylthiolated residue; phosphorylated residue; monohydroxylated residue
Instrument	LTQ Orbitrap; 4800 Proteomics Analyzer; Agilent instrument model

Revision	Datetime	Status	ChangeLog Entry
0	2013-06-10 03:41:19	ID requested
1	2013-07-24 02:42:42	announced
1	2014-07-25 01:15:04	announced
⏵ 2	2013-07-24 07:32:35	announced	Add reference

Johansson HJ, Sanchez BC, Mundt F, Forshed J, Kovacs A, Panizza E, Hultin-Rosenberg L, Lundgren B, Martens U, M, á, th, é G, Yakhini Z, Helou K, Krawiec K, Kanter L, Hjerpe A, St, å, l O, Linderholm BK, Lehti, ö J, Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer. Nat Commun, 4():2175(2013) [pubmed]

submitter keyword: Human, breast cancer, tamoxifen, drug resistance, subcellular fractionation, IPG-IEF, nLC-MS

Henrik J Johansson
contact affiliation	Dept. Oncology/pathology, Karolinska Institute
contact email	henrik.johansson@ki.se

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