Abstract 5663: Clinical relevance of unfolded protein response (UPR) signaling in breast cancer

Abstract

Abstract Background: Protein homeostasis as regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Due to the exposure of chronic stressors, cancer cells learn to adapt to prolonged ER stress by creating pro-survival alterations in the UPR signaling pathway and subsequently drive carcinogenesis. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be recognized with pathological progression, mutational accumulation, clinical stage advancement, and survival in breast cancer. Methods: A total of 5,316 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis (GSVA) and median was used to divide high vs low score groups in each cohort. Results: High UPR breast cancer significantly enriched not only cell proliferation-related gene sets (E2F targets, G2M checkpoint, MYC target v1 and v2, and MITOTIC spindle), but also other pro-cancerous gene sets, including MTORC1 signaling, DNA repair, PI3K/AKT/MTOR signaling, and reactive oxygen species pathway, consistently in both METABIC and GSE96058 cohort (all false discovery rate < 0.25). Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal cells, T cells, B cells, and myeloid cells (p < 0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) consistently in both cohort (all p < 0.001). High UPR breast cancer was significantly associated with worse patient survival in both cohort (all p < 0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but not in HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was significantly infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells consistently in both cohorts (all p < 0.001). On the other hand, high UPR ER-positive/HER2-negative breast cancer was significantly infiltrated with high level of stromal cells, including fibroblasts, adipocytes, and endothelial cells in tumor microenvironment (all p < 0.001). Finally, high UPR metastatic breast cancer was also significantly associated with worse patient survival (p = 0.041). Conclusion: UPR signaling is associated with cancer aggressiveness, and with worse survival in breast cancer, especially ER-positive/HER2-negative breast cancer subtype. Citation Format: Masanori Oshi, Shipra Gandhi, Rongrong Wu, Akimitsu Yamada, Li Yan, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Clinical relevance of unfolded protein response (UPR) signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5663.