Importantly, HIF1α, but not HIF2α, is constitutively hyperactivated in TNBC even under a normoxic environment ( 17), which suggests that coordinated positive and negative regulatory mechanisms control HIF1α activity to ensure that this stress response is tightly regulated under normal nutrient conditions. In addition, although the HIF1α-induced glycolytic switch is an important acute adaptive response for cancer growth, chronic and sustained activation of this switch is rather detrimental ( 16). However, extensive and prolonged HIF1α activity leads to distinct pathologic responses in many tissues ( 14, 15). HIF1 acts as a networking hub to coordinate activities of multiple signaling molecules that influence tumorigenesis ( 13).
Intriguingly, one of the defining features of TNBC is the increased expression of a large battery of genes that are regulated by HIF1α ( 11, 12). However, the molecular defect for hypoglycemia in EBF1-deficient mice and the functional role of EBF1 in tumorigenesis remain unclear. Recently, it has been reported that EBF1 contributes to cancer progression by negatively regulating the p53 signaling pathway or modulating telomerase reverse transcriptase expression ( 9, 10). EBF1 levels are relevant in leukemia ( 8). EBF1 also plays a role in malignant transformation. Notably, EBF1 knockout mice are hypoglycemic and have an increased metabolic rate and increased energy expenditure ( 7). In addition to regulating embryonic neural development and the adult nervous system, EBF1 is expressed at high levels in adipocytes and functions as a key integrator of signal transduction, inflammation, and metabolism ( 4– 6). EBF1 plays important roles in developmental processes, including cell fate decisions, cell differentiation, and cell migration ( 3). Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.Įarly B cell factor 1 (EBF1) was first discovered in early B cells and is one of the key factors in B cell differentiation ( 2). EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC.
Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). However, the functional roles of EBF1 in tumorigenesis remain elusive. Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism.
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