Abstract 1512: EGR1 regulates phenotypic plasticity to promote breast cancer progression upon metabolic stress through elaborating HERPUD1-mediated unfolded protein response

Abstract Uncontrolled proliferation is one of the most important hallmarks of cancer. Consequently, cancer cells exhibit a high demand for oxygen and nutrients from the tumor microenvironment. Nonetheless, cancer cells in the core region of a solid tumor often undergo nutrient and oxygen deficiency owing to the restricted vascularization, ultimately leading to the occurrence of metabolic stress. To survive under stress, series of stress response will be activated, providing opportunities for cancer cells to confront unfavorable circumstances and further developing phenotypic plasticity. Without altering genetic sequence, phenotypic plasticity enables cancer cells to adjust their behavior to survive from stress. This critical ability of cancer cells is orchestrated by multiple stress response under different stress stimuli, but its regulatory mechanism upon metabolic stress still requires further investigation. We identified a transcription factor EGR1 that is rapidly induced upon metabolic stress in breast cancer (BC). Known as an immediate early gene, EGR1 can be upregulated by multiple types of stimulation and further regulates tumor progression. Through cell viability and anoikis assay, we found that EGR1 could promote BC cell survival upon metabolic stress under both attach and detach condition. Furthermore, through xenograft tumor model, we noticed the inhibitory effect of EGR1 on tumor growth was more obvious in the late phase of tumor development, when metabolic stress mostly occurred. These results demonstrated the role of EGR1 in regulating phenotypic plasticity to promote BC cell growth upon metabolic stress. To identified genes regulated by EGR1 upon metabolic stress, EGR1-based ChIP-Seq was performed, and further compared with glucose deprivation RNA-Seq data to identify overlapping genes. Being the most upregulated overlapping gene upon glucose deprivation, HERPUD1 was chosen for further validation. HERPUD1 has been found to be important for degrading unfolded or misfolded protein in unfolded protein response (UPR). However, the role of HERPUD1 upon metabolic stress remains elusive. We found HERPUD1 expression significantly increased upon metabolic stress and was higher in EGR1 knockdown (KD) cells, suggesting EGR1 was a transcriptional suppressor upon metabolic stress. As a critical stress response to promote phenotypic plasticity, UPR was diminished in EGR1 KD cells due to higher expression of HERPUD1, potentially explaining the increased vulnerability of these cells to metabolic stress. Collectively, EGR1 was identified as a transcription factor significantly upregulated upon metabolic stress. By suppressing HERPUD1 expression, EGR1 maintained UPR at an optimal level, which promoted the development of phenotypic plasticity of BC cells and assisted cells to survive and thrive from metabolic stress. Citation Format: Yi-Zhen Wu, Ge-Jyun Liu, Shan-Ting Lei, Wei-Huan Zeng, Mei-Ju Juan, Yu-Shu Liu, Yong-Han Su, David K. Ann, Ching-Ying Kuo. EGR1 regulates phenotypic plasticity to promote breast cancer progression upon metabolic stress through elaborating HERPUD1-mediated unfolded protein response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1512.