Abstract
Comprehensive multiplatform analysis of Luminal B breast cancer (LBBC) specimens identifies two molecularly distinct, clinically relevant subtypes: Cluster A associated with cell cycle and metabolic signaling and Cluster B with predominant epithelial mesenchymal transition (EMT) and immune response pathways. Whole-exome sequencing identified significantly mutated genes including TP53, PIK3CA, ERBB2, and GATA3 with recurrent somatic mutations. Alterations in DNA methylation or transcriptomic regulation in genes (FN1, ESR1, CCND1, and YAP1) result in tumor microenvironment reprogramming. Integrated analysis revealed enriched biological pathways and unexplored druggable targets (cancer-testis antigens, metabolic enzymes, kinases, and transcription regulators). A systematic comparison between mRNA and protein displayed emerging expression patterns of key therapeutic targets (CD274, YAP1, AKT1, and CDH1). A potential ceRNA network was developed with a significantly different prognosis between the two subtypes. This integrated analysis reveals a complex molecular landscape of LBBC and provides the utility of targets and signaling pathways for precision medicine.