BackgroundMetabolic　reprogramming　is　a　hallmark　in　cancer.　Pyrimidine　metabolism　(PM),　a　part　of　nucleotide　metabolism,　has　been　shown　to　be　associated　with　the　progression　of　various　cancers,　and　the　prognostic　predictive　ability　of　pyrimidine　metabolism-related　genes　(PMG)　in　breast　cancer　has　not　been　elucidated.　This　paper　was　designed　to　identify　pyrimidine　metabolism-related　prognostic　marker　of　breast　cancer　and　potential　targeted　therapeutic　options.MethodsThe　cohort　in　the　TCGA-BRCA　dataset　was　used　for　patient　information,　and　108　pyrimidine　metabolism-related　genes　were　identified　from　the　MSigDB　KEGG　pathways.　We　identified　PM　clusters　in　breast　cancer　and　established　a　PM　risk　score　model　based　on　10　pyrimidine　metabolism-related　genes.　The　status　of　immune　infiltration　was　assessed　in　different　groups.　Further　we　identified　the　relevant　hub　gene　and　analyzed　its　significance　for　breast　cancer　metastasis　and　explored　patterns　of　combination　therapy.ResultsWe　identified　three　types　of　PM　clusters　in　breast　cancer　and　clarified　that　PM　cluster　C　with　inferior　prognosis　possessed　activation　of　tumor　proliferation-associated　pathways.　The　high-risk　group　in　PM　risk　score　model　was　found　to　be　characterized　by　an　immunosuppressive　microenvironment.　The　hub　gene　POLR2C　(RNA　polymerase　II　subunit　C)　was　further　identified　and　verified　as　a　potential　prognostic　marker.　Furthermore,　targeting　POLR2C　in　combination　with　anti-PD-1　and　anti-angiogenic　therapies　demonstrated　a　promising　tumor　suppression　effect,　suggesting　a　potential　therapeutic　direction.ConclusionsThese　findings　provide　additional　insights　into　the　link　between　breast　cancer　and　PMG,　offering　potential　strategies　for　breast　cancer　management　and　treatment.