Background: Chronic psychosocial distress may accelerate breast cancer progression by altering immune, and inflammatory pathways, yet its genome-wide transcriptional effects in breast tumors remain unclear. This study uses RNA sequencing (RNA-seq) to characterize how distress influences transcriptional programs within the breast tumor microenvironment (TME). Methods: Tumor samples from the Women's Health after Breast Cancer Study were analyzed for genome-wide transcriptional effects of distress. Participants completed the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression Scale (CES-D) at diagnosis, including total scores and subscales (somatic symptoms, depressive affect, interpersonal problems, and positive affect). RNA-seq was performed on FFPE tumors from 195 women (152 ER+, 43 ER−). Principal component analysis (PCA) identified distress domains contributing to transcriptional variability. Participants were classified using PSS (>14 vs 0-14) and CES-D somatic symptoms (>3 vs ≤3). Differential gene-expression and gene-set enrichment analyses evaluated high-stress/low-somatic symptoms and low-stress/high-somatic symptoms groups vs a common low-stress/low-somatic symptoms reference, adjusting for age and education. Statistical significance was defined as FDR<0.05. Results: PCA indicated subtype-specific distress signatures, with CES-D somatic symptoms explaining the most transcriptional variance in ER+ tumors and PSS explaining more variance in ER− tumors. In ER+ tumors, high stress with low somatic symptoms upregulated immune-activation pathways, including B-cell signaling, interferon responses, complement, and antigen presentation (top NES ~2.1-2.7, FDR<0.05). Key genes ( FLG, IGLV3-16, IGKV3D-15, RPS7P3 ) mapped to immune-activation and interferon pathways. In ER− tumors, high stress showed enrichment of PD-1 co-inhibition and MHC-I antigen-presentation (NES=2.36 and 2.15, respectively, FDR<0.03), with suppression of neuronal, metabolic, mitochondrial, and protein-synthesis signaling (NES −1.4 to −2.1, FDR<0.05). High somatic symptoms in ER+ tumors enriched translational and ribosomal pathways (NES=3.0, FDR<0.01). In ER− tumors, high somatic symptoms were associated with increased keratinization, leptin, WNT, and IGF signaling (NES~1.8-2.7, FDR<0.02), and reduced chromatin-regulation, DNA replication, RNA-processing, translation pathways, and MHC-I antigen presentation (NES ~1.8 to -1.9, FDR<0.006). Conclusions: Psychological distress shapes breast-tumor transcriptional programs in a subtype-specific manner. Stress and depressive domains map to distinct immune, metabolic, and biosynthetic pathways in ER+ vs ER− disease, suggesting that different forms of distress engage different processes in the TME. This information could be leveraged to design new treatments for patients.