The Sig27 multigene stratifies breast cancer fatality risk via reflecting tumor-associated immune suppressive features

• Sig27 predicts breast cancer prognosis as effective as Oncotype DX and Mammaprint. • Sig27 effectively assesses poor prognosis across 24 human cancer types. • Sig27 strongly associates with immune checkpoints (IC), TAM, Treg, and CD8Tex. • FPR3, LAMP3, and FAM65B correlate with breast cancer’s immunosuppressive features. • FPR3, LAMP3, FAM65B, CD274, TIGIT, and PVRIG are increased in advanced breast cancer. We evaluated the biomarker potential of Sig27, a 27-gene panel originating from prostate cancer, in breast cancer (BC). Orthotopic BC tumors were generated in Balb/c mice using 4T1 cells expressing either empty vector (EV) or the gain-of-function PCSK9 mutant D374Y. Sig27 expression was analyzed in mouse tumors, 13,103 primary BCs, 60 metastases, and 780 normal breast tissues. Its prognostic value was assessed in BC, 20 other cancer types, and in tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and exhausted CD8⁺ T cells (CD8Tex). Sig27 was significantly altered in D374Y vs. EV tumors and showed consistent dysregulation in primary and metastatic BCs. It stratified BC fatality risk comparably to OncotypeDX and MammaPrint. Notably, Sig27 predicted poor prognosis across 21 cancer types. In 2716 BCs, OncotypeDX and MammaPrint correlated with mitotic progression, while Sig27 was predominantly associated with immune regulation. In bulk RNA-seq datasets ( n = 6734), Sig27 and its key genes (FPR3, LAMP3, and FAM65B) were strongly associated with multiple immune checkpoints (ICs). Single-cell RNA-seq data revealed their primary expression in TAMs, and to a lesser extent in Tregs and CD8Tex. These associations were enhanced in Sig27IM, formed by FPR3, LAMP3, and FAM65B. Their expression, along with Pd-l1, Lgals9 , and Pvrig , was upregulated in D374Y tumors. Furthermore, Sig27 and Sig27IM predicted pathologic complete response in BC treated with PD1 and PD-L1 inhibitors; Sig27IM displayed robust correlations with established immune-signatures: CTL, Merck18, TIDE, and STAT1_sig. Collectively, Sig27 captures BC’s immune properties, which likely contribute to its biomarker potential.