Abstract
Abstract During tumor development and progression, cancer cells encounter cytotoxic conditions such as hypoxia, nutrient deprivation, and low pH due to inadequate vascularization. To maintain survival and growth in the face of these physiologic stressors, a set of adaptive stress response pathways are induced. One adaptive pathway well studied in other contexts is the unfolded protein response (UPR), which is induced by factors affecting the endoplasmic reticulum (ER). Triple negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options and TNBC-targeted therapies do not yet exist. We found that XBP1, a key component of the UPR, is activated in TNBC and plays a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. Depletion of XBP1 blocked primary tumor growth, inhibited tumor relapse and reduced the population of chemotherapy-resistant tumor initiating cells (TICs). Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 regulates the hypoxia response through controlling HIF1α transcriptional activity and the expression of HIF1α targets. Notably, we identified a gene expression signature indicative of XBP1 pathway activation that is associated with poor prognosis in two independent cohorts of patients with TNBC. Our findings reveal a key function for this branch of the UPR in TNBC, opening new therapeutic avenues for patients with TNBC. Citation Format: Chen X. Unfolding the unfolded protein response in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BS3-1.
Published Version
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