Date of Award
5-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Bioengineering
Committee Chair/Advisor
Brian Booth, Ph.D.
Committee Member
Terri Bruce, Ph.D
Committee Member
Angela Alexander-Bryant, Ph.D
Committee Member
Agneta Simionescu, Ph.D
Abstract
On a global scale, breast cancer remains the most commonly diagnosed cancer in the world. In 2020 alone, there were over 2.3 million new cases of breast cancer seen and a total of 685,000 deaths globally, this represents 16% or 1 in every 6 cancer deaths seen in women. By 2040 it is projected that the breast cancer burden will rise by over 40% to exceed 3 million new cases a year. Further understanding of the underlying biology and mechanisms behind tumor progression and breast cancers such as HER2+ breast cancer would allow for new therapeutic treatment targets to emerge. HER2+ breast cancers represent 20% of all breast cancer subtypes and HER2 hyperactivity is correlated with oncogenic outcomes. The overexpression of HER2 is primarily due to gene amplification of HER2. Therefore, investigation of 1) mechanisms that cause cancer cells to be tumorigenic and 2) how cells lose their ability to cause malignant formations, would propel advancements in mechanistic insight of the complex disease.
In this study we sought to gain mechanistic insight through investigation of extracellular vesicles (EVs) and exosomes in the mammary microenvironment (MM). Exosomes are a subset of extracellular vesicles (ranging in size from 30–200-nm in diameter) which serve as biomolecular snapshots of their cell of origin; they play key roles in biological processes including cell metastasis and homeostasis. The MM has been shown to direct non-mammary cells to participate in normal gland development. This cellular redirection has also been seen in tumorigenic cells such that cancer cells lose their tumor-forming capacity and post-differentiation assume a normal non-tumorigenic fate. This phenomenon has been named “cancer cell redirection.” Though cell redirection previously was achieved both in vivo and in vitro, there is still a significant gap in understanding what drives redirection mechanistically. Investigation of EVs influencing redirection is critical for elucidating the mechanisms behind redirection and identifying new targets for treatment.
In this work we characterize isolated EVs derived from normal mammary epithelial cells, HER2+ breast cancer cells, and EVs derived from cancer cells that have undergone redirection. Through comparative analysis of EVs which were involved in intercellular signaling we reveal unique biomarkers and specific candidate pathways influencing cancer cell redirection. We identified unique features within redirected cells and pathways associated with tumorigenic activity. High Throughput Next Gen RNA Seq analysis was also employed on exosomes of interest to identify miRNAs and whole transcriptome differentially expressed genes/gene profiles. Additionally exosome release inhibition and contact dependency for tumorigenic phenotype suppression was also investigated. Our findings present a novel analysis on extracellular vesicle and exosome influence on HER2+ breast cancer cell redirection and reveal biomarkers and therapeutic target candidates to be investigated in future studies.
Recommended Citation
Okereke, Brenda, "Mammary Epithelial Cell Derived Extracellular Vesicles Influence Tumorigenic Phenotype Suppression In HER2-Positive Breast Cancer Cells" (2024). All Dissertations. 3560.
https://open.clemson.edu/all_dissertations/3560