Date of Award

Fall 9-23-2025

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmacology and Experimental Therapeutics

First Advisor

Irida Kastrati

Second Advisor

Simon Kaja

Abstract

Despite similar breast cancer incidence rates, African American (AA) women experience a 40% higher mortality rate compared to Caucasian American (CA) women. This disparity is multifactorial and particularly pronounced in the Chicago area. AA women are twice as likely to be diagnosed with triple-negative breast cancer (TNBC), often at a younger age and with more aggressive disease. TNBC is a heterogeneous subtype lacking targeted therapies and is associated with the poorest prognosis among breast cancer types. Therefore, there is an urgent need for novel therapeutic strategies for TNBC, especially those tailored to AA patients. The thioredoxin pathway is essential for maintaining redox homeostasis and supports various cellular processes, including proliferation, cell death, and signaling. In cancer, the heightened reliance on this pathway presents a druggable vulnerability. In this study, we investigated the role of thioredoxin reductases (TXNRDs), with a particular focus on the mitochondrial isoform TXNRD2, in AA-derived TNBC cell models. We first observed that TXNRD2 levels are highest in breast tumors from AA patients. We then evaluated the therapeutic potential of targeting TXNRD2 using a new class of non-covalent TXNRD inhibitors, TXNRD(i)s, which bind an allosteric site rather than relying on traditional covalent inhibition. To distinguish the activity of TXNRD2 from its close homologue TXNRD1, we developed a dual-labeling live-cell microscopy approach. Silencing TXNRD2 using siRNA significantly impaired TNBC cell growth. While TXNRD1 also plays a role in supporting TNBC cell viability, dual silencing of TXNRD1 and TXNRD2 had a markedly stronger inhibitory effect, with minimal impact on non-tumorigenic MCF-10A control cells. Treatment of AA-derived TNBC cells with our TXNRD(i)s phenocopied this dual silencing, and our imaging data confirmed that these compounds act as pan-TXNRD1/2 inhibitors. Together, these findings support TXNRD2 as a viable therapeutic target in TNBC and suggest that simultaneous inhibition of both TXNRD1 and TXNRD2 may represent a more effective therapeutic strategy especially for treating AA-patients with lethal breast cancers.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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