Grants and Contracts Details
Basal-like breast cancer (BLBC) is a devastating form of breast cancer with limited therapeutic options. During tumor progression and metastasis, tumor cells rewire the metabolic programming, resulting in enhanced nutrient uptake to supply energetic and biosynthetic pathway under hypoxia condition. It is important for tumor cells to activate mitophagy to deal with metabolic crisis and maintain the mitochondrial homeostasis. How BLBC maintains metabolic and mitochondrial homeostasis through fine-tuning mitochondrial biogenesis and mitophagy to adapt the hypoxia microenvironment remains elusive. We found that EBF1 is highly expressed in BLBC. Knockdown of EBF1 induced extensive mitophagy and eventually serve cell death. Interestingly, silencing of HIF1-alpha blocks EBF1 deficiency-induced mitophagy and cell death in BLBC. In addition, we found that HIF1-alpha induced EBF1 expression while EBF1 interacted with HIF1-alpha and inhibited HIF1-alpha activity. Based on these preliminary data, we posit that EBF1 functions as a “mitochondrial homeostasis checkpoints” to ensure metabolic homeostasis through regulating HIF1-alpha activity, which, when compromised, can contribute to imbalanced mitochondrial and massive mitophagy in BLBC. Our strategy will be to first delineate the role of EBF1 in BLBC (aim 1); then determine the molecular mechanisms between EBF1 and HIF1-alpha (aim 2); and to characterize the role of EBF1 in vivo using mice model and human sample. The knowledge gained from these studies will increase our understanding about the fundamental biology of relationship between metabolic reprogramming and mitochondrial homeostasis, particular in hypoxia. Our works also reveal a pivotal function for the EBF1 in BLBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
|Effective start/end date||9/1/18 → 8/31/24|
- National Cancer Institute: $1,725,439.00
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