Simple SummaryBreast cancer is the leading cause of cancer deaths in women. The current management of patients with breast cancer needs improvement in two aspects: risk estimation, which forms the basis for treatment, and effective therapies. In our research, we discovered taxifolin to inhibit breast cancer via increasing the expression of 36 genes. These genes, as a group, effectively predict the death probability in patients with breast cancer. Importantly, aggressive breast cancers are frequently associated with increases in the 1q21.3 DNA region, which is home to theHNRN,KPRP,CRCT1, andFLG2genes. These four genes can inhibit breast cancer, and their expressions are induced by taxifolin, revealing a novel mechanism by which taxifolin suppresses breast cancer. This study thus advances our ability in relation to the risk estimation and treatment of breast cancer. Through using taxifolin as a nutritional supplement, our research reveals an intriguing application of taxifolin in the clinical management of patients with breast cancer.AbstractTaxifolin inhibits breast cancer (BC) via novel mechanisms. In a syngeneic mouse BC model, taxifolin suppressed 4T-1 cell-derived allografts. RNA-seq of 4T-1 tumors identified 36 differentially expressed genes (DEGs) upregulated by taxifolin. Among their human homologues, 19, 7, and 2 genes were downregulated in BCs, high-proliferative BCs, and BCs with high-fatality risks, respectively. Three genes were established as tumor suppressors and eight were novel to BC, includingHNRN,KPRP,CRCT1, andFLG2. These four genes exhibit tumor suppressive actions and reside in 1q21.3, a locus amplified in 70% recurrent BCs, revealing a unique vulnerability of primary and recurrent BCs with 1q21.3 amplification with respect to taxifolin. Furthermore, the 36 DEGs formed a multiple gene panel (DEG36) that effectively stratified the fatality risk in luminal, HER2+, and triple-negative (TN) equivalent BCs in two large cohorts: the METABRIC and TCGA datasets. 4T-1 cells model human TNBC cells. The DEG36 most robustly predicted the poor prognosis of TNBCs and associated it with the infiltration of CD8+ T, NK, macrophages, and Th2 cells. Of note, taxifolin increased the CD8+ T cell content in 4T-1 tumors. The DEG36 is a novel and effective prognostic biomarker of BCs, particularly TNBCs, and can be used to assess the BC-associated immunosuppressive microenvironment.