Understanding the Mechanism of Cancer Therapeutic SAH5-EJ1 in Targeting Breast Cancer Metastasis
Author
Soyfer, Eli MichaelIssue Date
2020Advisor
Schroeder, Joyce A.
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The University of Arizona.Rights
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.Abstract
While many breast cancer subtypes overexpress members of the ERBB family of receptor tyrosine kinases (including the Epidermal Growth Factor Receptor/EGFR, HER2, ERBB3 and ERBB4), only HER2 has been effectively targeted. Evidence indicates that established therapeutics against EGFR targeting either the extracellular domain or the kinase domain fail due to unique biological activities of the receptor in breast cancer. In light of this, a stapled peptide mimicking the EGFR juxtamembrane domain (SAH5-EJ1) was developed and found to induce complete tumor regression in a model of inflammatory breast cancer (SUM149/NODSCID). SAH5-EJ1 was found to induce both necrosis and apoptosis through calcium and ROSdependent mechanisms, but the mechanism by which this was achieved was unknown. In the current study, we have evaluated EGFR-dependent calcium signaling as a means to promote cell death. We have discovered that SAH5-EJ1-induced cell death is dependent upon expression of both EGFR and the TRPV1 (transient receptor potential cation channel subfamily V member 1) calcium channel located on the plasma membrane. Mechanistically, SAH5-EJ1induces the activation of TRPV1, resulting in a dramatic influx of extracellular calcium. This is followed by a sharp rise in cellular reactive oxygen species (ROS) into the cell and induction of cell death. These data demonstrate a reliance of EGFR on calcium signaling in breast cancer survival, one which can be effectively targeted in breast cancer.Type
textElectronic Thesis
Degree Name
M.S.Degree Level
mastersDegree Program
Graduate CollegeMolecular & Cellular Biology