Document Type
Dissertation
Date of Award
12-2024
School/College
College of Pharmacy and Health Sciences (COPHS)
Degree Name
Ph.D. in Pharmaceutical Science
Committee Chairperson
Yun Zhang, Ph.D.
Committee Member 1
Ya Fatou Njie Mbye, Ph.D.
Committee Member 2
Erica Cassimere, Ph.D.
Committee Member 3
Bin Liu, Ph.D.
Abstract
Subtype. Specifically, NCP172 and NCP245 tumors grew faster and were predominantly triple- negative than NCP245. RNA sequencing identified many differentially expressed genes (DEGs) between tumor and mammary gland controls. Ingenuity Pathway Analysis (IPA) of the DEGs revealed that pathways like Deubiquitination, Cell Cycle Checkpoints, RHO GTPase cycle, and HIF1α Signaling were associated with aggressive tumor characteristics, with heightened pathway activity in NCP172 likely contributing to greater growth and invasiveness.
This study further examined how different cells-of-origin contribute to breast cancer heterogeneity by inducing mutant p53 in either mammary myoepithelial or luminal cells. Tumors originating from myoepithelial cells (Tk5) exhibited a higher incidence and LOH frequency than those from luminal cells (Tk8), alongside an elevated prevalence of triple-negative subtypes. Pathway analysis of DEGs between tumors and mammary gland controls highlighted upregulated pathways such as ERK/MAPK signaling and immune-related pathways, aligning with the aggressive behavior observed in Tk5 in comparison to the Tk8.
In summary, the findings from this dissertation work reveal that mutant p53 cooperates with HER2 to promote breast tumor growth, increase prevalence of triple-negative subtypes, and significantly alter metastasis patterns. Additionally, the behavior and molecular characteristics of mutant p53 driven tumors are heavily influenced by their cells-of-origin, with myoepithelial and luminal cells giving rise to distinct tumor profiles. Understanding both the genetic mutations driving breast cancer and the cellular context in which they occur is essential. The findings offer new perspectives on the cooperation between HER2 and mutant p53 and the role of cellular origin, providing valuable insights for developing more personalized therapeutic strategies for this heterogeneous disease.
Copyright
Copyright © for this work is retained by the author. Any documents and information presented are protected by copyright under US Copyright laws and are the property of the author. All Rights Reserved. For permission to use this content please contact the author or the Graduate School at Texas Southern University ([email protected]).
Recommended Citation
Williams-Villalobo, Abie, "Breast Cancer: HER2-Mutant P53 Cooperation and The Cell-Of-Origin Dependent Dynamics" (2024). Dissertations (2016-Present). 101.
https://digitalscholarship.tsu.edu/dissertations/101