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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA230758-02
Application #
9720915
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Salnikow, Konstantin
Project Start
2018-09-01
Project End
2023-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526