Abstract
Proteogenomic approaches have enabled the generat̲ion of novel information levels when compared to single omics studies although burdened by extensive experimental efforts. Here, we improved a data-independent acquisition mass spectrometry proteogenomic workflow to reveal distinct molecular features related to mammographic appearances in breast cancer. Our results reveal splicing processes detectable at the protein level and highlight quantitation and pathway complementarity between RNA and protein data. Furthermore, we confirm previously detected enrichments of molecular pathways associated with estrogen receptor-dependent activity and provide novel evidence of epithelial-to-mesenchymal activity in mammography-detected spiculated tumors. Several transcript–protein pairs displayed radically different abundances depending on the overall clinical properties of the tumor. These results demonstrate that there are differentially regulated protein networks in clinically relevant tumor subgroups, which in turn alter both cancer biology and the abundance of biomarker candidates and drug targets.
Highlights
Breast cancer (BC) is the most common female malignancy
BC is associated with increasing incidence rates, but the mortality is steadily decreasing due to better patient care, the availability of new treatment options, and a deeper understanding of the mutational and molecular dynamics of each breast cancer type.[1,2]
Given the fact that transcript/protein expression and regulation is dependent on upstream regulators of cell biology, we argued whether Food and Drug Administration (FDA) drug target transcript−protein correlations were dependent on the ER status
Summary
Breast cancer (BC) is the most common female malignancy. BC is associated with increasing incidence rates, but the mortality is steadily decreasing due to better patient care, the availability of new treatment options, and a deeper understanding of the mutational and molecular dynamics of each breast cancer type.[1,2] BCs are broadly classified according to the status of the estrogen and progesterone receptors (ER and PgR), the receptor tyrosine kinase ERBB2 and Ki67. The study by Bouchal et al identified the protein markers INPP4B, CDK1, and ERBB2 as discriminatory of key BC histopathological features (e.g., lymph-node status), pinpointed pathways that relates to tumor phenotypes, and assessed the degree of similarity between transcript and protein abundance.[14] In DIA MS (or sequential window acquisition of all theoretical mass spectra (SWATH)15,16), consistent peptide/protein identification rates is achieved across samples via DDA-based spectral libraries. We improved a previously established DIA MS-based proteogenomic workflow and used the workflow on a breast cancer cohort to identify molecular pathways related to breast cancer biology and mammographic appearances. The most notable feature was related to the enrichment of the epithelial-to-mesenchymal transition (EMT) pathway in spiculated tumors These findings are in line with the concept that protrusions, i.e., spiculae form the invading front of the cancer, can remodel the surrounding healthy breast tissue
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