Date of Award

8-8-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Bioinformatics

First Advisor

Antiño Allen

Abstract

Over 310,000 new cases of breast cancer will be diagnosed in 2024, making it the most commonly diagnosed cancer in United States women. Advancements in treatment options such as chemotherapy and radiation have resulted in a 5-year survival rate of 91%. With nearly 4.1 million breast cancer survivors living in the United States today, there is a need for a better understanding of the long-term side effects of these treatments and the impact these may have on the quality of life for these survivors. Reported in up to 78% of cancer patients who received chemotherapy, chemotherapy induced cognitive impairment (CICI), or “chemobrain”, is defined as an impairment in memory, learning, executive function, and attention following chemotherapy treatment. In this study, the behavior and cognitive effects of the combination chemotherapy treatment of Doxorubicin (Dox), Cyclophosphamide (CYP), and Paclitaxel (PTX) (AC-T) was evaluated. 12-week-old female C57/BL6 mice were treated with 8 once weekly intraperitoneal injections (IP) of either AC-T (DOX 2mg/kg, CYP 50mg/kg, PTX 5mg/kg) or saline (0.9% sodium chloride). 30 days after the last AC-T injection, mice underwent the three-chamber sociability test to assess social behavior and social memory. In the final stage of the test, AC-T treated mice spent equal time with both the novel and the stranger mouse, indicating a deficit in social memory. Changes in dendritic spine structure and morphology has been correlated with altered hippocampal brain function. Golgi-Cox staining was used to visualize these changes. There were no significant changes in dendritic complexity or spine morphology in the CA2 region of the hippocampus. Immediate Early Genes (IEGs) are genes that are rapidly transcribed during learning and behavior tasks. Western blot analysis was conducted to identify alterations the expression of IEGs such as Arc, c-Fos, and Egr-1. RNA sequencing was performed to evaluate changes in gene expression after chemotherapy treatment. 85 differentially expressed genes were identified, 62 of which were down regulated in AC-T treated mice. Among these downregulated genes, we identified 6 that are associated with neurogenesis and the regulation of neurotransmitter levels, and these genes were validated using RT-qPCR.

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