Accurate classification of breast tumors is vital for patient management decisions and enables more precise cancer treatment. Here, we present a quantitative proteotyping approach based on sequential windowed acquisition of all theoretical fragment ion spectra (SWATH) mass spectrometry and establish key proteins for breast tumor classification. The study is based on 96 tissue samples representing five conventional breast cancer subtypes. SWATH proteotype patterns largely recapitulate these subtypes; however, they also reveal varying heterogeneity within the conventional subtypes, with triple negative tumors being the most heterogeneous. Proteins that contribute most strongly to the proteotype-based classification include INPP4B, CDK1, and ERBB2 and are associated with estrogen receptor (ER) status, tumor grade status, and HER2 status. Although these three key proteins exhibit high levels of correlation with transcript levels (R > 0.67), general correlation did not exceed R = 0.29, indicating the value of protein-level measurements of disease-regulated genes. Overall, this study highlights how cancer tissue proteotyping can lead to more accurate patient stratification.

• Klíčová slova
• SWATH-MS, breast cancer, data independent acquisition, proteomics, tissue, transcriptomics, tumor classification,
• MeSH
• fosfatasy genetika   metabolismus   MeSH
• lidé MeSH
• nádory prsu klasifikace   metabolismus   patologie   MeSH
• proteinkinasa CDC2 genetika   metabolismus   MeSH
• proteom analýza   metabolismus   MeSH
• proteomika metody   MeSH
• receptor erbB-2 genetika   metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• rychlé screeningové testy MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CDK1 protein, human MeSH Prohlížeč
• ERBB2 protein, human MeSH Prohlížeč
• fosfatasy MeSH
• phosphatidylinositol-3,4-bisphosphate 4-phosphatase MeSH Prohlížeč
• proteinkinasa CDC2 MeSH
• proteom MeSH
• receptor erbB-2 MeSH
• receptory pro estrogeny MeSH

BACKGROUND: The initial pharmacokinetic study of a new anticancer agent (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum (IV) (LA-12) was complemented by proteomic screening of rat plasma. The objective of the study was to identify new LA-12 target proteins that serve as markers of LA-12 treatment, response and therapy monitoring. METHODS: Proteomic profiles were measured by surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS) in 72 samples of rat plasma randomized according to LA-12 dose and time from administration. Correlation of 92 peak clusters with platinum concentration was evaluated using Spearman correlation analysis. RESULTS: We identified Retinol-binding protein 4 (RBP4) whose level correlated with LA-12 level in treated rats. Similar results were observed in randomly selected patients involved in Phase I clinical trials. CONCLUSIONS: RBP4 induction is in agreement with known RBP4 regulation by amantadine and cisplatin. Since retinol metabolism is disrupted in many cancers and inversely associates with malignancy, these data identify a potential novel mechanism for the action of LA-12 and other similar anti-cancer drugs.

• Publikační typ
• časopisecké články MeSH