Author ORCID Identifier

https://orcid.org/0000-0002-0657-1811

Date of Award

8-10-2021

Degree Type

Closed Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Dr. Ritu Aneja

Second Advisor

Dr. Zhi Ren Liu

Third Advisor

Dr. Christos Hatzis

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. This lack of expression of therapeutic targets renders the treatment of TNBC challenging. In addition to high aggressiveness and tumor heterogeneity, TNBC displays profound racial disparities, with African American (AA) women experiencing worse outcomes than European American (EA) women. The molecular mechanisms underlying racial disparities in TNBC remain largely unknown, and their elucidation may pinpoint druggable targets to improve treatment outcomes in AAs with TNBC. In this study, I used different in vitro and in vivo preclinical models to identify and validate novel therapeutic targets to treat TNBC using small molecule kinase inhibitors. Survivin, an antiapoptotic protein encoded by BIRC5, was identified as a critical driver of racial disparities in TNBC. Notably, the extent of phosphorylation of survivin by the kinases PLK1 and AURKB was found to be a key determinant of TNBC disparity. Inhibition of PLK1 and AURKB using volasertib and barasertib, respectively, strongly inhibited TNBC cell proliferation. The non-essential kinesin motor protein KIFC1 (also known as HSET) was identified as another critical driver of racial disparities in TNBC. Specifically, KIFC1 was found to interact with MYH9 to promote proliferation and metastasis in AA TNBC. KIFC1 inhibition using CW069 strongly suppressed the metastatic potential of TNBC cells. Similar to breast cancer, prostate cancer (PCa) is characterized by high tumor heterogeneity and extensive metabolic rewiring. In this study, the lipid-based drug monoethanolamine (Etn) was found to alter membrane dynamics and GLUT1 membrane trafficking, thereby decreasing glucose uptake. This intracellular glucose deprivation and mitochondrial dysfunction induced metabolic stress and promoted apoptosis in PCa cells. The findings of this study strongly suggest that i) survivin phosphorylation is an essential post-translational modification promoting proliferation in AA TNBC cells, ii) KIFC1 is a critical player in TNBC metastasis, and iii) Etn-induced GLUT1 recycling impairment and glucose deprivation promotes apoptosis in PCa cells. These findings collectively reveal novel strategies to optimize targeted therapies and precision medicine approaches in breast cancer and PCa.

DOI

https://doi.org/10.57709/23983888

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