Date of Award

January 2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

First Advisor

Scott Garrett

Second Advisor

Emilie Vomhof-DeKrey

Abstract

This dissertation explores the role of Schlafen (SLFN) family proteins in Triple-Negative Breast Cancer (TNBC), a subtype known for its aggressive behavior and poor response to treatment. Through a series of studies, this dissertation examines the interplay between multiple SLFN proteins, chemotherapy resistance, and immune modulation, revealing the potential of SLFN12 as both a biomarker and therapeutic target for improving treatment outcomes, particularly in overcoming chemoresistance in TNBC.

Breast cancer, the most common cancer worldwide, includes various subtypes like TNBC, which lacks estrogen, progesterone, and HER2 receptors, making it resistant to conventional therapies. SLFN proteins, first discovered in mice, regulate immune responses, cell differentiation, and viral infections, with specific members like SLFN5, SLFN11, and SLFN12 influencing cancer progression and chemotherapy sensitivity. These proteins, which are interferon-stimulated, can serve as biomarkers and predictive factors for treatment response. Chapter 1 provides an in-depth examination of the underlying concepts surrounding breast cancer and the role of SLFN family proteins.

Chapter 2 reviews current immunotherapy approaches for TNBC, noting promising responses to PD-1/PD-L1 inhibitors, although their efficacy remains limited. Chapter 3 reveals a novel signaling cascade among SLFNs during IFN-α2 treatment in TNBC, indicating a complex regulatory network influencing cell viability and suggesting potential targets for therapy. Chapter 4 features SLFN12's role in enhancing chemotherapy sensitivity, especially to taxanes and anthracyclines, and its potential as a biomarker for chemotherapy responsiveness.

Chapter 5, the conclusion of this dissertation, underscores the pivotal role of SLFN proteins, particularly SLFN12, in modulating immune responses and chemotherapy resistance, offering promising targets for future TNBC therapies.

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