Date of Award

7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Francesca-Fang Liao, Ph.D.

Committee

Meiyun Fan, M.D, Ph.D.; Kui Li, M.D, Ph.D.; Ramesh Narayanan, Ph.D.; Edwards A. Park, Ph.D.

Keywords

chemoresistance; inflammation; LUBAC; NF-kB; OTULIN; TNF-alpha

Abstract

Triple negative breast cancer (TNBC) is aggressive but cannot be treated with hormone therapy or molecular therapy due to the lack of a target. Chemotherapy is a systemic treatment that works by attacking rapidly growing cells, which is initially more effective for TNBC patients than those individuals with the hormone receptor-positive breast cancer. However, patients with TNBC tend to develop resistance to chemo drugs, called chemoresistance. After years of effort, the signaling pathways involved in TNBC chemoresistance are gradually revealed, including the nuclear factor-kappa B (NF-kB) pathway. Transcription factor NF-kB is widely involved in cancer development and progression, and its overactivation renders chemoresistance to TNBC and induces aberrant inflammation. Therefore, targeting NF-kB becomes a feasible strategy to overcome chemoresistance. Ubiquitination is an essential post-translational modification during which ubiquitin chains are assembled on a substrate protein, leading to various cellular processes, such as endocytosis, membrane trafficking, DNA repair, signal transduction, and protein degradation. The outcome of one ubiquitinated protein is dependent on its ubiquitin linkage and the context. Our previous study has shown that the linear ubiquitin chains assembled by the linear ubiquitin chain assembly complex (LUBAC) solidly facilitate NF-kB signaling transduction upon genotoxic stress. OTU deubiquitinase with linear linkage specificity (OTULIN) is known to cleave linear ubiquitin chains exclusively. The purpose of this dissertation is to investigate whether OTULIN can counteract LUBAC-mediated NF-

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0003-4595-285X

DOI

10.21007/etd.cghs.2022.0600

Additional Files
2022-016-Li-DOA.pdf (177 kB)
Declaration of Authorship
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