Date of Graduation

8-2016

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Elsa R. Flores

Committee Member

Don L. Gibbons

Committee Member

Sendurai Mani

Committee Member

Kenneth Y. Tsai

Committee Member

Jeffrey Rosen

Abstract

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found that ΔNp63 is capable of modulating tumor development by regulating the epithelial mesenchymal transition. ΔNp63 does this through its role regulating microRNAs, in this case, miR-98 and miR-34a, which in turn regulate known EMT transcription factors Twist1 and Lef1. Alterations of ΔNp63 led to the development of various tumor types, among them mammary adenocarcinomas that were aggressive and highly metastatic. Focusing on this tumor type, we investigated ΔNp63’s role regulating mammary gland development. We found a striking phenotype where ΔNp63 loss led to increased proliferation in mammary epithelial cells but stunted gland growth and promoted structural disorganization. We complemented these findings with sequencing results; where we were able to identify several pathways such as EMT, cell polarity, ER signaling, and IGF signaling that are also altered upon ΔNp63 loss and could potentially explain both of the developmental and tumor phenotypes observed. In the end, shed light on the role of ΔNp63 as a modulator of cancer progression and on the pathways through which it could be doing this function. This information could potentially be used to identify novel targets and develop novel targeted cancer therapies that would greatly improve the lives of patients.

Keywords

DeltaNp63, p63, p53, metastasis, mouse models, breast cancer, mammary development, EMT, Cancer