Abstract
In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.
Highlights
In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches
Molecular characterization has progressively stratified breast cancer patients into more disease-type specific cohorts; with the first clinical manifestation being the adoption of immunohistochemical evaluation of ER, PR, KI67, and later HER2 expression as primary determinants of treatment regimens
To date, unbiased proteome profiling has not resolved a consistent variance with mRNA profiling across known breast tumor subtypes
Summary
Molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Research efforts over the preceding decades have led to immense progress in our understanding of the molecular heterogeneity of tumors originating in the same tissue, solidifying a long-proposed idea that single effective organ-oforigin specific treatments are not adequate. This realization fostered the need for in-depth molecular characterization to stratify patients into treatment courses that target their individually unique tumors. Parallel advancements in high-throughput protein quantification techniques have enabled the burgeoning of protein-based molecular characterization of breast tumors In theory, these classifications are a more accurate reflection of functional heterogeneity and stronger predictors of therapeutic response, as cellular function and pharmaceutical intervention are largely mediated at the protein level. Proteogenomics studies link aberrations observed at the protein level to genomic events or properties, such as mutations, insertions/deletions, substitutions, and single-nucleotide polymorphisms[4,5,10,11]
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