Proteogenomic approaches have enabled the generat̀²ion 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.