It is well known that cancer metabolism is highly dynamic and context- and oncogene-dependent. However, the underlying mechanism, particularly that of interorganelle communication in oncogene-dependent metabolic reprogramming, is largely unknown. Our preliminary studies establish that oncogenic MYC regulates Endoplasmic Reticulum (ER)-localized transmembrane sensor IRE1? and its substrate XBP1 via multiple mechanisms. Importantly, our pilot studies suggest the increased susceptibility of MYC-overexpressing triple negative breast cancer (TNBC) to IRE1?/XBP1 inhibition, possibly mediated via altered interorganelle communication and metabolic reprogramming to fatty acid oxidation (FAO). These findings provide a framework to seek biological insight into this altered communication between the ER, mitochondria, and nucleus in MYC-overexpressing TNBC cells, and to further explore the effects of pharmacological inhibition of IRE1? as an anti-tumor approach for MYC-driven TNBC by disrupting the interorganelle communication. We hypothesize that oncogenic MYC hijacks the ER stress sensor IRE1?, and its substrate XBP1, to promote mitochondrial FAO and sustain TNBC tumorigenesis and resistance to chemotherapy. This proposal will elucidate the function and mechanism of the ER in regulating MYC-driven oncogenic stress and mitochondrial metabolic reprogramming in TNBC.
In Aim 1, we will investigate the biological significance of IRE1?/XBP1 mediated ER-nucleus communication in MYC-driven TNBC.
Aim 2 will determine the role of mitochondrial FAO activation by the IRE1?/XBP1 pathway in MYC-driven TNBC. Lastly, Aim 3 will investigate the in vivo efficacy and mechanisms of combination therapy with IRE1? inhibitor and docetaxel in treating MYC-driven TNBC. The resulting data from this proposal will be significant as they will promote the development of novel, mechanism- based therapeutic approaches to disrupt these altered metabolic pathways and improve the treatment of MYC- driven TNBC.
Triple-negative breast cancer is the most lethal form of breast cancer, and currently, it has no approved targeted therapy. Our research will establish a novel therapeutic strategy to target the interorganelle communications in MYC-driven TNBC and improve patient outcome. !