The University of Chicago received a $667,792 Project Grant award from the National Cancer Institute (NCI) under the Cancer Treatment Research program (CFDA 93.395). The goal of this 5-year grant is to develop highly potent and pharmacologically stable synthetic transcriptional repressors (STRs) that can directly inhibit the oncogenic activities of the stress-induced transcription factors XBP1 and HIF1A in triple-negative breast cancer (TNBC). The research will map how these optimized STRs reprogram hypoxia-induced, XBP1/HIF-dependent gene expression and oncogenic phenotypes in TNBC cells. The project will also test the efficacy of the STRs in inhibiting TNBC tumor growth, metastasis, and chemoresistance using in vitro and in vivo models. This work aims to provide insights into the molecular mechanisms of adaptive stress responses in TNBC and establish the potential of directly targeting XBP1/HIF1A-driven transcription as a therapeutic strategy.