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Title page for ETD etd-03172016-102302

Type of Document Dissertation
Author Youngblood, Victoria Marie
URN etd-03172016-102302
Title The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutaminolysis in HER2-positive Breast Cancer
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Barbara Fingleton Committee Chair
Jin Chen Committee Member
Melissa Skala Committee Member
Rebecca Cook Committee Member
  • breast cancer
  • ephrin-A1
  • EPHA2
  • glutaminolysis
  • glutamine metabolism
  • tumor metabolism
Date of Defense 2016-02-19
Availability unrestricted
Dysregulation of receptor tyrosine kinases (RTKs) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2+ subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. This thesis sought to determine the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We integrated in vivo and in vitro models of HER2-overexpressing breast cancer to demonstrate that loss of ephrin-A1 leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo. Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 was attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the Ephrin-A1/EPHA2 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency.
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