Author ORCID Identifier

https://orcid.org/0000-0001-5161-1133

Date of Graduation

5-2018

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Elsa R. Flores, Ph.D.

Committee Member

Dihua Yu, M.D., Ph.D.

Committee Member

Pierre McCrea, Ph.D

Committee Member

Brian Davis, Ph.D

Committee Member

David McConkey, Ph.D

Abstract

p63 is a member of the p53 family, a well-known tumor suppressor which is considered the guardian of the genome. The TP63 gene encodes multiple isoforms that can be categorized into two main isoforms, TAp63 and ΔNp63, which are expressed in different cellular compartments and have distinct functions in many biological processes. While the Flores laboratory identified TAp63 as a tumor and metastasis suppressor, the precise roles of ΔNp63 isoforms in tumorigenesis and metastasis remain elusive. ΔNp63 is the predominant p63 isoform expressed in the epidermis and plays essential roles in regulating epidermal development and homeostasis. Utilizing a ΔNp63-conditional knockout mouse model generated in the Flores lab, I demonstrated that the loss of ∆Np63 in basal epidermal cells elicits an “irreversible” epithelial to mesenchymal transition (EMT) via activation of EMT-associated transcription factors, leading to a delay in wound healing process in vivo. Moreover, my work revealed pleiotropic roles of ΔNp63 as either a tumor suppressor or an oncogene in tumor development and progression. Further, I showed that ΔNp63 activates its oncogenic program through transcriptional regulation of Lef1 in breast cancer and lung squamous cell carcinoma. Finally, by generating an in vivo ΔNp63-inducible knockdown system, I demonstrated that a dynamic regulation of ΔNp63 enhances metastatic dissemination in breast cancer. Taken together, my work clarified complex context-dependent roles of ΔNp63 in modulating EMT, cancer progression and metastasis. These findings revealed novel regulatory networks of ΔNp63 in normal wound repair and cancers, which are particularly beneficial for the development of diagnostic biomarkers and therapeutic interventions for chronic wounds and metastatic cancers.

Keywords

p63, wound healing, metastasis, breast cancer, EMT

Available for download on Saturday, April 27, 2019

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