Date of Award

5-2026

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Bioengineering

Committee Chair/Advisor

Heather W. Dunn

Committee Member

Angela Alexander-Bryant

Committee Member

Jessica Larsen

Abstract

One in eight women in the United States will develop breast cancer in their lifetime. However, women of predominantly African ancestry encounter one of the most severe forms of breast cancer, triple-negative breast cancer (TNBC), at nearly double the incidence and mortality rates of other ancestry groups. TNBC is characterized by high rates of metastasis, metabolic reprogramming, chemoresistance, and recurrence, collectively contributing to exceptionally poor patient outcomes. How patients’ genetic backgrounds interplay with TNBC-permissive factors and metabolic reprogramming patterns has been underexplored to date, limiting ancestry-informed treatment options. This work aims to better characterize ancestry-specific TNBC gene expression and metabolic variations to shape a pilot study of ancestry-informed TNBC treatment in vitro, leveraging both small interfering ribonucleic acid (siRNA) and established chemotherapeutics.

To characterize potential targets for our ancestry-informed TNBC therapy, bulk RNA-seq datasets from ex vivo breast cancer samples of either African or European ancestry were assembled into cohorts by ancestry and subtype. Differential expression analysis among these cohorts revealed around 100 transcripts of interest that were significantly up- or downregulated in TNBC cases from women of African ancestry compared to those of European ancestry. Ontological assessment revealed that the most significant expression patterns were those implicated in promoting aberrant tumor cell metabolism. Real-time TNBC metabolism was investigated by conducting extracellular flux analysis across eight cell lines of interest from patients of either ancestry group. Basal metabolic profiles and responses to metabolic inhibitors confirmed the heterogeneous phenotypes of TNBC, but comparisons against the metabolisms of mammary epithelial cells and HER2+ breast cancer cells between ancestry groups suggested potential TNBC metabolic vulnerabilities. Thus, with metabolic reprogramming implicated as one of the most defining factors of TNBC in patients of African ancestry, we designed a combination therapy of siRNA and chemotherapy to address this central finding. Our siRNA molecule, capable of transiently silencing expression of a target gene via transcript degradation, was designed to reduce TNBC mitochondrial plasticity and to sensitize this traditionally chemoresistant subtype to platinum-based chemotherapy. Preliminary coadministration of our siRNA and a platinum-based chemotherapeutic to TNBC in vitro indicates a synergistic potential for ancestry-informed TNBC treatment and future precision oncology applications.

Author ORCID Identifier

0009-0003-0718-8069

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Available for download on Monday, May 31, 2027

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