DOI
https://doi.org/10.25772/MGSH-3G33
Defense Date
2025
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmacology & Toxicology
First Advisor
Imad Damaj
Second Advisor
Aron Lichtman
Third Advisor
Paula Bos
Fourth Advisor
Elizabeth Barrows
Abstract
Aromatase inhibitors (AIs) are widely used as adjuvant treatments of estrogen receptor-positive breast cancer but are frequently associated with aromatase inhibitor musculoskeletal syndrome (AIMSS), a condition characterized by joint pain, myalgia, and reduced physical activity. Despite its prevalence, the underlying mechanisms of AIMSS remain poorly understood. In this study, we investigated whether inflammation contributes to AIMSS and evaluated interleukin- 17A (IL-17A) as a potential therapeutic target. Using an ovariectomized female mouse model treated with letrozole, the most commonly prescribed AI, we performed cytokine profiling across multiple tissues. We observed significant increases in IL-17A and other pro-inflammatory markers in blood serum, dorsal root ganglia, spinal cord, and knee joint synovial tissue, with IL- 17A notably elevated in three of the four tissues examined. Behavioral assays revealed that antibody-mediated blockade of IL-17A protein reversed letrozole-induced mechanical hypersensitivity, reduced grip strength, and diminished voluntary behaviors such as nesting and wheel running in a dose-dependent manner. In contrast, blocking the IL-17A receptor produced only partial and short-lived improvements, primarily in grip strength and nesting behavior. These findings identify IL-17A as a key mediator of AIMSS and suggest that targeting IL-17A signaling may offer a promising therapeutic approach to alleviate AI-associated side effects in breast cancer patients.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-4-2025