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.　Wholeexome　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.