Abstract 3583: Distinct breast cancer gene signatures by estrogen receptor status associated with psychological distress.

Abstract 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. Citation Format: Shipra Gandhi, Sayeeda Yasmeen, Spencer Rosario, Wiam Bshara, Thaer Khoury, Hans Minderman, Orla Maguire, Zhihong Gong, Ayana T. Ruffin, Megan Meek Wyatt, Mahmoud Abdelbary, Chrystal Mary Paulos, Elizabeth Repasky, Pawel Kalinski, Christine Ambrosone, Song Yao, Chi-Chen Hong. Distinct breast cancer gene signatures by estrogen receptor status associated with psychological distress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3583.