Semester

Summer

Date of Graduation

2020

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Julie Lockman

Committee Member

Hangang Yu

Committee Member

Werner Geldenhuys

Committee Member

Peter Guida

Committee Member

Malcolm Mattes

Abstract

ABSTRACT

The preliminary background that puts this research into context is threefold; it is the aggressive nature of triple negative breast cancer (TNBC), the complexity surrounding its pathology, and the significant lack of targeted treatment for this disease. To clarify the focus of my research, I have concentrated on identifying a targeted treatment for TNBC. In the process, I have identified cycles of reciprocity between treatment, clinical diagnosis, staging, and pathology that will be addressed in smaller papers. However, the weight of this work is in the discovery of a novel target for triple negative breast cancer. The value of this research is evidenced by the significant discovery of a novel ion channel target that demonstrates selective, targeted destruction of TNBC without damage to healthy tissue. The specific research aims and objectives are to first, characterize the big conductance calcium and voltage gated potassium channel (BK) in TNBC to investigate the apparent contradiction of a depolarized (more positive) resting membrane potential within the context of a membrane with overexpression of channels that cause hyperpolarization (more negative) in the membrane potential. Secondly, examine hyperpolarization of TNBC cells as the mechanism of cell death by severe efflux of potassium (K) from the TNBC cell via these overexpressed BK channels. Thirdly, establish the first steps for human translational research of this discovery with evaluation of human TNBC tumor biopsies for similar overexpression of this BK channel. In summary, the objectives are to fill the knowledge gap by demonstrating BK channels are not functional (active) in TNBC [which explains why we can have a positive (depolarized) cell that should be more negative (hyperpolarized) due to the overexpression of the BK channel but is not]. Secondly, demonstrate that this overexpression of non-functioning (not-active) channels can be exploited by activating those channels and hyperpolarizing the cells with efflux of their potassium from the cell as a mechanism for selective (not impacting healthy cells), targeted treatment for TNBC. Finally, translating that to a first step evaluation of human TNBC from tumor biopsies.

The additional supportive papers in the scope of this work are in chapter two and chapter four surrounding the main work in chapter three. The supportive work in chapter two exists to identify the opportunity for electrophysiology as a tool for translating basic science discovery to clinical application and is listed as reference [1]. The supportive work in chapter four exposes an epidemiologic discovery of a translational gap in the clinical diagnosis of triple negative breast cancer (manuscript under review) where ion channels can impact. This dissertation interpolates information from the afore mentioned papers by the author. As described, chapter two references material from reference [1] and was authored as follows: Gina Sizemore1, Brandon Lucke-Wold2, Charles Rosen2, James W. Simpkins3, Sanjay Bhatia2, and Dandan Sun4. Chapter three references material from the main body of work and was authored as follows: Gina Sizemore1, Sarah McLaughlin2, Mackenzie Newman3, Kathleen Brundage4, Amanda Ammer2, Karen Martin2, Elena Pugacheva5, James Coad6, Malcolm D. Mattes7, Han-Gang Yu3. Finally, chapter four supports the research with the transition to epidemiology and references material authored as follows: Gina Sizemore1, Toni Rudisill2.

In summary, this composition weaves a thread across the clinical translational science field intertwining chapter two (paper 1) a methods paper of ion channels and the electrophysiology tool, with chapter three (paper 2) the novel discovery of an ion channel target, and the epidemiologic opportunity for ion channel translation in chapter four (paper 3).

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