DPYSL3 is a mutifunctional modulator in claudin-low breast cancer

Abstract

Proteogenomics is the field of integrating data from mass spectrometry-based shotgun proteomics, and phosphoproteomics into next-generation RNA and DNA sequencing data analysis pipelines that promises new insights into cancer biology and therapeutic targeting. As well as analyses of clinical samples for disease phenotype association analysis, the application of proteogenomics to model systems also has considerable potential. Patient-derived xenografts (PDX) generated in immunosuppressed mice strains provide a useful setting to analyze the biological properties of the intrinsic subtypes of breast cancer because this approach effectively captures the biological diversity of this disease [1]. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) generated quantitative i-TRAQ mass spectrometry-based proteomics and phosphoproteomics data across the WHIM series of PDXs tumors that was combined with RNA and DNA sequencing information to provide integrated proteogenomic profiles [2]. Herein we explored these data to identify extreme outliers in the proteogenomic data that were Claudin-low (CLOW) subtype-specific and had not previously studied in breast cancer. WHIM12 breast cancer PDX was previously classified as a high confidence CLOW tumor based on transcriptomic profiling [2]. A CPTAC proteogenomic analysis prioritized dihydropyrimidinaselike-3 (DPYSL3) as a multi-level (RNA/Protein/Phosphoprotein) expression outlier specific to the CLOW subset of triple negative breast cancers. These data suggested high-levels of DPYSL3 expression and hyper-phosphorylation were associated with CLOW breast cancer and thus DPYSL3 may regulate some of the unique biological features of this subtype. In our view, discovery approaches that trangulate multiple tiers of ‘omics data with literature search engines to identify novel and targetable cancer biology should be more widely applied.