Date of Award

2023

Degree Name

Biomedical Sciences

College

College of Science

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Travis Salisbury, Committee Chairperson

Second Advisor

Dr. Richard Egleton

Third Advisor

Dr. Piyali Dasgupta

Fourth Advisor

Dr. Joshua Hess

Fifth Advisor

Dr. Sandrine Pierre

Abstract

Cancer is one of the leading causes of death worldwide, responsible for over half a million deaths each year. There are multiple risk factors associated with the development of cancer. Some of these risks include genetics, smoking, and most recently, obesity (Lewandowska et al., 2019) (De Pergola & Silvestris, 2013). Research has shown that obesity is linked to the promotion of fourteen different cancers, including aggressive triple negative breast cancer (TNBC). Patients that are obese are more likely to develop cancer (Park et al., 2014). In addition, if the patient is obese at the time of a cancer diagnosis, they tend to have a larger tumor size and higher tumor grade (Neuhouser et al., 2015; Thompson et al., 2021; Yang et al., 2011). According to the world health organization, 41.9% of the world’s population is obese. While the link between obesity and its impact on the clinical outcome of cancer has been made, the mechanism by which obesity promotes cancer remains understudied, especially in TNBC. TNBC is the deadliest form of breast cancer due to the limited amount of treatment options and aggressive phenotype. The role of obesity in TNBC remains understudied compared to estrogen receptor positive breast cancer. This work provides insight into the role of obesity on the pathogenesis of TNBC. In this study deidentified peritumor breast adipose tissue was obtained from breast cancer patients being treated by the Edwards Comprehensive Cancer Center. Peritumor breast adipose tissue was cultured in cell culture media for 24 hours, and media containing adipose tissue secretions was collected. Peritumor breast adipose tissue obtained from patients with BMIs > 30 were deemed high BMI adipose-derived secretome (ADS), conversely, BMI < 30 was deemed low BMI ADS. TNBC MDA-MB-231 and MDA-MB-436 cells were treated with high BMI ADS or low BMI ADS in serum free media. Cell migration and invasion assays were performed on treated TNBC cells. Images were taken at time 0, and 24 hours to assay changes in cell migration with Image J software. Treated TNBC cells were then processed for western blot analysis to determine changes in the levels and activity of signaling pathways.

This work is the first to characterize the effects of BMI on human peritumor adipose tissue on TNBC cells, demonstrating a novel new system for studying the effect of obesity on peritumor ADS regulation of TNBC cell signaling and invasiveness. In addition, we investigate the effect of BMI on the regulation of signaling and invasiveness of TNBC cells by peritumor breast adipose tissue secreted factors. We hypothesize that high BMI ADS has a stronger cancer promoting effect on TNBC cells than low BMI ADS and this could in part underly the mechanism by which obesity promotes TNBC progression.

Subject(s)

Breast – Cancer – Patients.

Breast – Cancer – Causes.

Obesity – Cancer.

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