Investigating the Role of the ABL Kinase regulated HIF-1a-TAZ Signaling Pathway in the Promotion of Brain Metastasis

Duke University, Durham NC

Investigators

Abstract

ABSTRACT Brain metastasis leads to cognitive decline and is associated with increased cancer patient morbidity and mortality. The hypoxic microenvironment of brain metastases, as well as the presence of the blood-brain barrier, makes these tumors difficult to treat. Current therapies to treat brain metastases are ineffective and lack durable responses. Therefore, mechanistic understanding of the underpinnings required for brain metastasis promotion is needed for the development of novel therapeutic strategies. Hypoxia Inducible Factor-1 (HIF-1) is the master regulator of the hypoxia response and is upregulated in hypoxic areas, including brain metastases. It was reported that increased HIF-1 signaling correlated with enhanced proliferation of breast cancer metastases in the brain, and breast cancer brain metastases patient specimens exhibited increased HIF-1 expression compared to matched primary breast tumors. We have identified a potential functional interaction of HIF-1 with TAZ, a transcriptional co-activator in the Hippo signaling pathway. Here we propose to evaluate the hypothesis that this interaction regulates expression of a subset of target genes that promote brain metastasis in triple- negative breast cancer (TNBC). Notably, we recently found that the Abelson (ABL) family kinases regulate the expression and activity of HIF-1 in breast cancer cells. We have identified a novel ABL-dependent pathway whereby an E3-ligase targets HIF-1α for degradation in the presence of ABL kinase inhibitors in hypoxia in TNBC. Previous work uncovered ABL kinase mediated regulation of TAZ. Thus, we will evaluate whether ABL- dependent activation of HIF-1 and TAZ in brain metastases leads to enhanced expression of unique transcriptional targets, and whether inhibition of ABL-mediated HIF-1 and TAZ activation impairs brain metastases in TNBC. The proposed research is expected to reveal novel mechanistic insights on the modulation of HIF-1 activity and crosstalk with TAZ downstream of ABL-mediated kinase regulation and elucidate the role of HIF-1 in the promotion of breast cancer brain metastasis.