Abstract
Abstract CEBPD (C/EBP delta) is a member of the CCAAT-enhancer binding protein (C/EBP) family of transcription factors characterized by a b-Zip domain that mediates dimerization and DNA binding. CEBPD is induced in response to acute stressors such as cytokine stimulation, bacterial lipopolysaccharide (LPS), corticosteroids, radiation and hypoxia. We have previously reported that CEBPD has dual functions in breast cancer by both attenuating or enhancing oncogenic pathways depending on context (Balamurugan and Sterneck, 2013, Mendoza-Villanueva et al., 2016). Recent studies reveal that elevated Endoplasmic Reticulum (ER) stress is associated with the pathology of several diseases including cancer. Limiting supply of nutrients and oxygen in growing tumor cells disrupts the protein folding homeostasis resulting in activation of the unfolded protein response (UPR). The UPR includes pathways that support adaptation to stress, and that are also implicated in promoting malignant features and therapy resistance in breast cancer. Hence, we investigated a possible role for CEBPD in this stress response pathway. Using breast cancer cell lines as model systems, we found that CEBPD is dynamically regulated in response to chemical and physiological inducers of ER stress. Kinetic analyses indicate that CEBPD induction is concurrent with the activation of the UPR effectors XBP1s and ATF4 suggesting a potential role in stress adaptation. Examination of the global transcriptional prolife of the Thapsigargin-induced stress response in MDA MB-231 cells indicated that CEBPD activates genes involved in cytokine and chemokine production/signaling, immune cell recruitment as well as angiogenesis pathways. While XBP1s has been previously ascribed to activating these pathways, the levels of activated XBP1 were not affected by CEBPD silencing. This is the first report of a similar role for CEBPD in the ER stress response and warrants the investigation of possible co-operation of CEBPD and XBP1 in the UPR pathway. Further, we show that knock down of CEBPD in cancer cells increased PARP cleavage and susceptibility to ER stress induced cell death. CEBPD deficient cells also displayed reduced LC3II accumulation, suggesting impaired autophagy induction in response to ER stress. Taken together, our data suggests that CEBPD is a novel proximal effector of the ER stress response in breast cancer cells. Activation of this transcription factor regulates tumor promoting inflammatory and angiogenic signaling pathways. Additionally, CEBPD expression confers a survival advantage to cancer cells encountering ER stress. Therefore, we propose that targeting CEBPD may sensitize cancer cells to ER stress inducing therapeutics. Citation Format: Namratha Sheshadri, Shikha Sharan, Esta Sterneck. CEBPD is an early endoplasmic reticulum stress response gene implicated in breast cancer cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4501. doi:10.1158/1538-7445.AM2017-4501
Published Version
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