Abstract P4-07-23: Piezo1 is associated with worse prognosis along with promoted epithelial-mesenchymal transition and hypoxia as well as less anti-cancer immune cells in hormone receptor (HR)-negative breast cancer
Authors: Eriko Katsuta, Kazuaki Takabe, Mateusz Opyrchal
Journal: Cancer Research (2022)

Abstract Introduction: Piezo1 is a transmembrane protein, forming a mechano-sensitive ion channel. Piezo channels play an important role in mechano-sensing and mechano-transduction. Stretch activation of Piezo channels lead to influx of cations and activation of additional Ca2+ channels and depolarization. There are early evidences that Piezo1 channel signaling alters cancer cell behavior. It promotes migration in breast cancer cells, migration and chemo-resistance in gastric cancer cells, invasion of osteosarcoma cells, and enhances cell survival in synovial sarcoma cells. Contrary, lower level of Piezo1 associates with more invasive phenotype in lung cancer. In this study, we aimed to investigate clinical relevance of Piezo1 expression in breast cancer. Methods: In order to investigate Piezo1 clinical relevance in breast cancer patients, we used The Cancer Genome Atlas (TCGA) breast cancer cohort as a testing cohort, and GSE3494 as validation cohort. Piezo1 expression levels were compared among different stages as well as breast cancer subtypes. Patients’ survival was compared based on Piezo1 expression in each subtype. Gene set enrichment analysis (GSEA) and cibersort algorithms were used to evaluate pathways and infiltrating immune cells associated with PIEZO1 expression. Results: There was no significant difference in PIEZO1 expressions based on AJCC stage (P=0.258). PIEZO1 expression was significantly higher in the hormone receptor (HR)-negative (both estrogen receptor (ER)- and progesterone receptor (PR)-negative) tumors (P&amp;lt;0.001), whereas, there was no significant difference between HER2-positive and -negative tumors (P=0.279). When we compared patient survival based on PIEZO1 expression, there was no significant difference in the whole breast cancer cohort (disease-free survival (DFS); P=0.201, overall survival (OS); P=0.694). On the other hand, high PIEZO1 expression showed significantly worse prognosis for both DFS (P=0.033) and OS (P=0.002) in the HR-negative cohort, but not in HR-positive cohort (DFS; P=0.995, OS; P=0.083). These findings were validated in validation cohort GSE3494, in which PIEZO1 expression was higher in the HR-negative patients as compared to its counterpart (P=0.006) and higher PIEZO1 showed worse prognosis in the HR-negative cohort (P=0.003). As possible mechanisms, GSEA revealed that PIEZO1 high expression tumor was associated with cancer aggressiveness characteristics, such as epithelial-mesenchymal transition (EMT) (P&amp;lt;0.001) and hypoxia (P&amp;lt;0.001) in HR-negative breast cancer. Further, PIEZO1 high expressing tumor has less anti-cancer immune cells, including activated CD4+ memory T cells (P=0.020) and CD8+ T cells (P=0.002). Conclusion: We found that PIEZO1 high expression was associated with poor prognosis in HR-negative breast cancer patients. It may be due to promoted EMT and hypoxic condition, as well as less immunogenic characteristics. Citation Format: Eriko Katsuta, Kazuaki Takabe, Mateusz Opyrchal. Piezo1 is associated with worse prognosis along with promoted epithelial-mesenchymal transition and hypoxia as well as less anti-cancer immune cells in hormone receptor (HR)-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-23.