Basal-like breast cancer (BLBC) is a devastating form with limited therapeutic options. During tumor progression and metastasis, tumor cells rewire their metabolism, which results in an enhanced nutrient uptake to supply the energetic and biosynthetic pathway under the hypoxic condition. It is important for tumor cells to activate mitochondrial selective autophagy (mitophagy) to avoid metabolic crisis and maintain the mitochondrial homeostasis. The means by which BLBC cells fine-tune mitochondrial biogenesis and mitophagy to maintain metabolic and mitochondrial homeostasis in order to adapt the hypoxic microenvironment, remain elusive. We found that EBF1 is highly expressed in BLBC. Knockdown of EBF1 induced extensive mitophagy, and eventual cell death. Interestingly, silencing HIF1? blocked the EBF1 deficiency-induced mitophagy and cell death in BLBC. In addition, we found that HIF1? induced EBF1 expression and that EBF1 interacted with HIF1? and inhibited HIF1? activity. Based on these preliminary data, we speculate that EBF1 functions as a safeguard to ensure metabolic homeostasis through a regulation of HIF1? activity, which, when compromised, can contribute to imbalanced mitochondria and massive mitophagy in BLBC. Our strategy will be to first delineate the role of EBF1 in BLBC (Aim 1); then determine the molecular interplay between EBF1 and HIF1? (Aim 2); and to characterize the role of EBF1 in vivo in human samples as well as in several mouse models (Aim 3). The knowledge gained from these studies will increase our fundamental understanding about biologic relationship between metabolic reprogramming and mitochondrial homeostasis, particular during hypoxia. Our work also reveals a pivotal function for the EBF1 in BLBC and suggests that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
Despite immense interest in metabolic reprogramming related to tumor progression, we still have little knowledge about how this process is balanced to maintain catabolic homeostasis, particularly during conditions of stress. By defining the role of EBF1 in regulation of HIF1? activity, this project will provide unique and new insight into how HIF1?-mediated metabolic reprogramming is regulated through EBF1.
