Degree
Doctor of Philosophy (PhD)
Department
Biological and Agricultural Engineering
Document Type
Dissertation
Abstract
Breast cancer is the most common type of cancer among all people in the United States as of 2023 and often has devastating impacts on afflicted patients. Although some treatments show great efficacy against primary breast tumors, none have been able to significantly reduce the mortality rate of breast cancer once it has metastasized to distant sites. In primary, hormone receptor-positive (HR+) breast cancers, endocrine therapies are often used as first-line treatments and are generally well-tolerated. However, as the disease progresses, these previously sensitive cancers can become resistant to endocrine therapies and continue proliferating despite them. Therefore, there is a need to understand the underlying mechanisms of the more aggressive behavior of HR+ breast cancer cells once metastasized. For a cancer cell to depart the primary site and reach a new tissue, the cell must undergo a multi-step process called the metastatic cascade. Researchers theorize that cancer cells develop mutations or altered phenotypes during the metastatic cascade due to the external mechanical stimuli, though it has yet to be determined in which step of the cascade these stimuli occur. Possibly the largest amount of mechanical stimuli is felt by the metastatic tumor cells in the circulation step of the metastatic cascade, mainly in the form of fluid shear stress (FSS). Here we suggest that stimuli such as FSS cause the circulating tumor cells (CTCs) to undergo the biological and molecular alterations underlying the change in behavior seen in metastatic settings. We hypothesize that exposing hormone receptor-positive breast cancer cells to a physiologically relevant magnitude (10 dynes/cm2) of fluid shear stress will downregulate hormone receptor expression and increase the activation of pro-survival/proliferation cellular pathways. To test this hypothesis, the following specific aims were developed: 1) optimize fluidic device shearing methods, media conditions & collection timepoints and 2) investigate & characterize short- and long-term effects of FSS on representative luminal A breast cancer cell lines. Transcriptomic results demonstrated decreases in gene expression of hormone receptor genes and estrogen receptor-regulated genes. Proteomic results showed increases in mTOR and growth factor signaling pathway-related proteins.
Date
7-24-2023
Recommended Citation
Cuccia, Jonathan James, "Physiologically Relevant Fluid Shear Stress Induced Receptor Conversion in Hormone Receptor-Positive (HR+) Breast Cancer" (2023). LSU Doctoral Dissertations. 6246.
https://repository.lsu.edu/gradschool_dissertations/6246
Committee Chair
Monroe, W. Todd
Included in
Biochemical and Biomolecular Engineering Commons, Biological Engineering Commons, Biomedical Informatics Commons, Molecular, Cellular, and Tissue Engineering Commons, Other Biomedical Engineering and Bioengineering Commons