Dataset Information

AN-A0FL-01A_BH-A0DG-01A_AN-A0AS-01A_phospho

ABSTRACT: TCGA Cancer Proteome Study of Breast Tissue, Phospho Enrichment, iTRAQ, AN-A0FL-01A_BH-A0DG-01A_AN-A0AS-01A

INSTRUMENT(S): QExactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast

DISEASE(S): Breast Carcinoma

SUBMITTER: Nathan J. Edwards

PROVIDER: PAe004758 | PeptideAtlas | 2015-12-31

REPOSITORIES: PeptideAtlas

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			Action	DRS
	PAe004758_10329_tandem.params	Other
	PAe004758_README	Other
	PAe004758_Search_Results_10329_201512191436.properties	Other
	PAe004758_Search_Results_10329_201512191436.tar.gz	Other
	PAe004758_mzXML_201512191432.properties	Other

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Publications

The CPTAC Data Portal: A Resource for Cancer Proteomics Research.

Edwards Nathan J NJ Oberti Mauricio M Thangudu Ratna R RR Cai Shuang S McGarvey Peter B PB Jacob Shine S Madhavan Subha S Ketchum Karen A KA

Journal of proteome research 20150504 6

The Clinical Proteomic Tumor Analysis Consortium (CPTAC), under the auspices of the National Cancer Institute's Office of Cancer Clinical Proteomics Research, is a comprehensive and coordinated effort to accelerate the understanding of the molecular basis of cancer through the application of proteomic technologies and workflows to clinical tumor samples with characterized genomic and transcript profiles. The consortium analyzes cancer biospecimens using mass spectrometry, identifying and quantif ...[more]

PMID: 25873244

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Project description:<a href="https://pdc.esacinc.com/pdc/browse/filters/study_name:TCGA_Breast_Cancer_Proteome|TCGA_Breast_Cancer_Phosphoproteome" target="_blank">Explore This Study at the NCI Proteomic Data Commons</a>Global proteome and phosphoproteome data have been acquired for 105 TCGA breast cancer samples using iTRAQ (isobaric Tags for Relative and Absolute Quantification) protein quantification methods. Samples were selected from each of the 4 breast tumor subtypes (Luminal A, Luminal B, Basal-like, HER2-enriched) described in the publication, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23000897" target="_blank">Comprehensive molecular portraits of human breast tumors (Cancer Genome Atlas Network, Nature 2012)</a>.Three TCGA samples and 1 common internal reference control sample are included in each iTRAQ experiment, consisting of 25 proteome and 13 phosphoproteome files. The internal reference is comprised of a mixture of 40 TCGA samples (of the 105 breast cancer samples) with equal representation of the 4 breast subtypes. Three of the TCGA samples have been assayed in duplicate for quality control purposes.05TCGA_AO-A12D-01A_AN-A04A-01A_BH-A0AV-01A_Proteome_BI iTRAQ proteome data were acquired twice, before (20130310) and after (20130416) maintenance of the Q Exactive MS system. The "20130416" dataset was used in the final publication (see <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S029" target="_blank">here</a>).Global proteome and phosphoproteome data were acquired for three normal breast samples in Experiment 37. Samples "263d3f-I", "blcdb9-I", and "c4155b-C" are normal breast tissue samples that were measured in the iTRAQ-114, -115, and -116 channels, respectively. All normal samples were compared to the internal reference sample in the iTRAQ-117 channel (see CPTAC, TCGA Breast Cancer iTRAQ Sample Mapping file below).Information on the complete TCGA Breast invasive carcinoma cohort (BRCA) can be found <a href="https://portal.gdc.cancer.gov/projects/TCGA-BRCA" target="_blank">here</a>. Genomic data for the 105 TCGA samples used in the CPTAC Proteome study can be downloaded from <a href="https://portal.gdc.cancer.gov/legacy-archive/search/f?filters=%7B%22op%22:%22and%22,%22content%22:%5B%7B%22op%22:%22in%22,%22content%22:%7B%22field%22:%22cases.project.program.name%22,%22value%22:%5B%22TCGA%22%5D%7D%7D,%7B%22op%22:%22in%22,%22content%22:%7B%22field%22:%22cases.project.project_id%22,%22value%22:%5B%22TCGA-BRCA%22%5D%7D%7D%5D%7D" target="_blank">here</a>.<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S015">https://cptac-data-portal.georgetown.edu/cptac/s/S015</a> on 10/15/18</li><li>Dataset source: <a href="https://pdc.esacinc.com/pdc/browse/filters/study_name:TCGA_Breast_Cancer_Proteome|TCGA_Breast_Cancer_Phosphoproteome" target="_blank">https://pdc.esacinc.com/pdc/browse/filters/study_name:...</a></li></ul>

Project description:<a href="https://pdc.esacinc.com/pdc/browse/filters/study_name:TCGA_Breast_Cancer_Proteome|TCGA_Breast_Cancer_Phosphoproteome" target="_blank">Explore This Study at the NCI Proteomic Data Commons</a><a href="http://www.nature.com/nature/journal/vaop/ncurrent/full/nature18003.html" target="_blank">Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P et al., Nature (2016) doi:10.1038/nature18003 Published online 25 May 2016</a>Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.Global proteome and phosphoproteome data have been acquired for 105 TCGA breast cancer samples using iTRAQ (isobaric Tags for Relative and Absolute Quantification) protein quantification methods. Samples were selected from each of the 4 breast tumor subtypes (Luminal A, Luminal B, Basal-like, HER2-enriched) described in the publication, Comprehensive molecular portraits of human breast tumors (Cancer Genome Atlas Network, Nature 2012).Three TCGA samples and 1 common internal reference control sample are included in each iTRAQ experiment, consisting of 25 proteome and 13 phosphoproteome files. The internal reference is comprised of a mixture of 40 TCGA samples (of the 105 breast cancer samples) with equal representation of the 4 breast subtypes. Three of the TCGA samples have been assayed in duplicate for quality control purposes.05TCGA_AO-A12D-01A_AN-A04A-01A_BH-A0AV-01A_Proteome_BI iTRAQ proteome data were acquired twice, before (20130310) and after (20130416) maintenance of the Q Exactive MS system. The "20130416" dataset was used in the final publication. The replicate dataset 05TCGA_AO-A12D-01A_AN-A04A-01A_BH-A0AV-01A_Proteome_BI_20130310_Replicate can be obtained <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S015" target="_blank">here</a>.Global proteome and phosphoproteome data were acquired for three normal breast samples in Experiment 37. Samples "263d3f-I", "blcdb9-I", and "c4155b-C" are normal breast tissue samples that were measured in the iTRAQ-114, -115, and -116 channels, respectively. All normal samples were compared to the internal reference sample in the iTRAQ-117 channel (see CPTAC, TCGA Breast Cancer iTRAQ Sample Mapping file below).Additional supplementary datasets are provided below that were too large to store at Nature Journal: <ul><li>Gene-by-Gene CNA-RNA and CNA-Protein Pearson correlations with p-values and Benjamini-Hochberg adjusted p-values</li><li>Phosphoproteome dataset "Phosphoproteome-P3": This table contains phosphosite iTRAQ log2 ratios for the 83 QC-passed samples (77 tumors + 3 tumor replicates + 3 normal breast samples). Phosphosite abundances are normalized (see Supplementary Methods, "Normalization").</li><li>Phosphoproteome raw files and datasets for PIK3CA- and TP53-mutant isogenic cell lines (TMT10-plex quantification; see Supplementary Methods)</li><li>Proteome Peptide Spectrum Match reports exported from Spectrum Mill for each of the 37 iTRAQ4 experiments, including the RefSeq FASTA file used for searches, and a Spectrum Mill quality metrics report</li></ul>Information on the complete TCGA Breast invasive carcinoma cohort (BRCA) can be found <a href="https://portal.gdc.cancer.gov/projects/TCGA-BRCA" target="_blank">here</a>. Genomic data for the 105 TCGA samples used in the CPTAC Proteome study can be downloaded from <a href="https://portal.gdc.cancer.gov/legacy-archive/search/f?filters=%7B%22op%22:%22and%22,%22content%22:%5B%7B%22op%22:%22in%22,%22content%22:%7B%22field%22:%22cases.project.program.name%22,%22value%22:%5B%22TCGA%22%5D%7D%7D,%7B%22op%22:%22in%22,%22content%22:%7B%22field%22:%22cases.project.project_id%22,%22value%22:%5B%22TCGA-BRCA%22%5D%7D%7D%5D%7D"target="_blank">here</a>.<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S029">https://cptac-data-portal.georgetown.edu/cptac/s/S029</a> on 08/28/19</li><li>Dataset source: <a href="https://pdc.esacinc.com/pdc/browse/filters/study_name:TCGA_Breast_Cancer_Proteome|TCGA_Breast_Cancer_Phosphoproteome" target="_blank">https://pdc.esacinc.com/pdc/browse/filters/study_name:...</a></li></ul>

Project description:Background Estrogen and progesterone are potent breast mitogens. In addition to steroid hormones, multiple signaling pathways input to estrogen receptor (ER) and progesterone receptor (PR) actions via posttranslational events. Protein kinases commonly activated in breast cancers phosphorylate steroid hormone receptors (SRs) and profoundly impact their activities. Methods To better understand the role of modified PRs in breast cancer, we measured total and phospho-Ser294 PRs in 209 human breast tumors represented on 2754 individual tissue spots within a tissue microarray and assayed the regulation of this site in human tumor explants cultured ex vivo. To complement this analysis, we assayed PR target gene regulation in T47D luminal breast cancer models following treatment with progestin (promegestone; R5020) and antiprogestins (mifepristone, onapristone, or aglepristone) in conditions under which the receptor is regulated by Lys388 SUMOylation (K388 intact) or is SUMO-deficient (via K388R mutation to mimic persistent Ser294 phosphorylation). Selected phospho-PR-driven target genes were validated by qRT-PCR and following RUNX2 shRNA knockdown in breast cancer cell lines. Primary and secondary mammosphere assays were performed to implicate phospho-Ser294 PRs, epidermal growth factor signaling, and RUNX2 in breast cancer stem cell biology. Results Phospho-Ser294 PR species were abundant in a majority (54%) of luminal breast tumors, and PR promoter selectivity was exquisitely sensitive to posttranslational modifications. Phospho-PR expression and target gene programs were significantly associated with invasive lobular carcinoma (ILC). Consistent with our finding that activated phospho-PRs undergo rapid ligand-dependent turnover, unique phospho-PR gene signatures were most prevalent in breast tumors clinically designated as PR-low to PR-null (luminal B) and included gene sets associated with cancer stem cell biology (HER2, PAX2, AHR, AR, RUNX). Validation studies demonstrated a requirement for RUNX2 in the regulation of selected phospho-PR target genes (SLC37A2). In vitro mammosphere formation assays support a role for phospho-Ser294-PRs via growth factor (EGF) signaling as well as RUNX2 as potent drivers of breast cancer stem cell fate. Conclusions We conclude that PR Ser294 phosphorylation is a common event in breast cancer progression that is required to maintain breast cancer stem cell fate, in part via cooperation with growth factor-initiated signaling pathways and key phospho-PR target genes including SLC37A2 and RUNX2. Clinical measurement of phosphorylated PRs should be considered a useful marker of breast tumor stem cell potential. Alternatively, unique phospho-PR target gene sets may provide useful tools with which to identify patients likely to respond to selective PR modulators that block PR Ser294 phosphorylation as part of rational combination (i.e., with antiestrogens) endocrine therapies designed to durably block breast cancer recurrence.