Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Abstract

Breast cancer remains the most diagnosed cancer in American women with a projected 44,000 women that will succumb to advanced metastatic disease in the next calendar year. Advanced and recurrent breast cancers frequently exhibit clinical resistance to therapeutic interventions including many that exhibit resistance against multiple drugs or therapies and results in chemoresistance. Chemoresistance, a common cause of therapeutic failure, can be classified as either innate or acquired, both of which result in dramatically different results following therapeutic intervention. Work in our laboratory has emphasized evaluating acquired chemoresistance against the microtubule-stabilizing drug, paclitaxel, and has demonstrated the ability to generate cells more resistant than cells treated with solvent controls. These paclitaxel resistant cells provide a critical model system for evaluating mechanisms of acquired chemoresistance. Findings from preliminary investigations of these chemoresistant cells indicate both novel growth patterns and dose-dependent reactions to paclitaxel. These changes in cellular behavior warrant further investigation as they imply a previously unreported mechanism of chemoresistance. To study acquired chemoresistance, it is necessary to have a model system. In the first part of my research (Chapter 2), I show that MDA-MB-231 cells respond to paclitaxel in a dose-dependent manner, and I create a long-term acquired paclitaxel resistant cell line. I then characterized this cell line and demonstrated that although they are resistant to paclitaxel their basic phenotypic traits remain unaltered. However, there are significant changes to these cells on a genotypic level which could be the beginning of investigation into the mechanisms of acquired chemoresistance. In the second part of my research (Chapter 3), I demonstrate that reducing expression of KIF14 within a triple-negative breast cancer (TNBC) cell line causes a reduction in cellular growth including proliferation potential and colony formation abilities. I also determine that when treated with paclitaxel, the TNBC cells are more responsive to paclitaxel treatment. When KIF14 expression is also reduced within resistant cells, they express a reduction in growth capabilities and are more responsive to paclitaxel treatment. This information thus provides a deeper understanding of KIF14s role in the mechanism of chemoresistance. Appearing in the third part of my research (Chapter 4), I find that epigallocatechin-3 gallate (ECGC) can suppress the growth of paclitaxel-resistant hormone responsive breast cancer cells in a dose-dependent manner. I also found that EGCG has the capacity to decrease the viability of paclitaxel resistant TNBC cells when treated with both EGCG and paclitaxel thus demonstrating the potential for this compound. This information thus supports further investigation into the molecular mechanisms of EGCG activity in paclitaxel-resistant cells and the potential as EGCG as a combinatorial treatment with paclitaxel.

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