Date of Award

Spring 5-6-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Ritu Aneja

Second Advisor

Zhi-Ren Liu

Third Advisor

Didier Merlin

Abstract

Women of African descent are disproportionately affected by breast cancer relative to European women. Africans and African-Americans are more likely to acquire aggressive breast cancer phenotypes such as triple negative breast cancer (TNBC), which lacks expression of pharmacologically-targetable targets such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Given breast cancer patients of African descent are predominantly triple negative, they are often refractory to hormone and HER2-targeted systemic therapies in the clinic, underlying their more aggressive disease course and poorer prognosis relative to women of other ethnic backgrounds. My work seeks to identify actionable biomarkers in patients of African descent, who are predominantly triple-negative and thus lack targeted treatment options and robust risk-predictive biomarkers. Herein, I present a three-pronged approach to examine inherent differences in tumor biology among racially-distinct breast tumors. I have examined surrogates of intratumor heterogeneity (mitotic propensity and centrosome amplification), the tumor immune microenvironment (tumor-infiltrating lymphocytes), and drivers of cell proliferation (human epidermal growth factor receptor family) among racially-distinct breast cancer patients and their potential as risk-prognostic biomarkers and alternative therapeutic targets. These facets of aggressive tumor biology have been linked to the acquisition of aggressive cellular phenotypes and drug resistance/relapse in breast cancer suggesting racial disparities in these biomarkers could perhaps be underlying the divergence in mortality rates. Furthermore, these key aspects of aggressive tumor biology (drivers of intratumor heterogeneity, tumor-infiltrating lymphocytes, and drivers of cell proliferation) can be evaluated in clinical samples using techniques such as immunohistochemistry and H&E staining as well as therapeutically targeted through rationally-designed agents such as putative centrosome declustering agents, immunotherapeutic intervention, monoclonal antibodies, and receptor agonists. Hence, my work suggests clinically-facile risk-prognostic and actionable biomarkers for patients of African descent, which may aid in reducing the global racial disparity in breast cancer. Furthermore, this work has broader clinical implications by extending prognostic biomarkers and actionable targets for aggressive breast cancer patients, irrespective of ethnicity, as well as paves the path for alternative avenues of addressing the global racially disparate burden in breast cancer such as metabolic, epigenetic, and proteomic approaches. Moreover, our work may further encourage the implementation of personalized treatment in the clinic based on each patient’s distinct tumor molecular profile.

DOI

https://doi.org/10.57709/14195356

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