Date of Graduation
12-2014
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Shiaw-Yih Lin
Committee Member
Dr. Jessica Tyler
Committee Member
Dr. Chun Li
Committee Member
Dr. Ju-Seog Lee
Committee Member
Dr. Hui-Kuan Lin
Abstract
Expression of the tumor suppressor protein BRCA1 is frequently lost in breast cancer patients, and the loss of its expression is associated with disruption of various critical functions in cells and cancer development. In the present study, we demonstrate through microarray analysis that cells with tumor suppressor candidate 4 (NPRL2/TUSC4) knockdown show critical changes to cell cycle, cell death pathways and a global impact on cancer development. More importantly, we observed a clear cluster pattern of NPRL2/TUSC4-knockdown gene profiles with established homologous recombination (HR) repair defect signature. Additionally, NPRL2/TUSC4 protein physically interacts with the E3 ligase HERC2 and prevents ubiquitin pathway-mediated BRCA1 degradation. Knockdown of NPRL2/TUSC4 expression enhanced BRCA1 polyubiquitination, leading to BRCA1 protein degradation and a marked reduction in HR repair efficiency. Conversely, ectopic expression of NPRL2/TUSC4 effectively suppressed the proliferation, invasion, and colony formation of breast cancer cells in vitro and tumorigenesis in vivo. Furthermore, knockdown of NPRL2/TUSC4 expression transformed normal mammary epithelial cells and enhanced the sensitivity of U2OS cells to the treatment of poly(ADP-ribose) polymerase inhibitors. Therefore, NPRL2/TUSC4 may act as a bona fide tumor suppressor by regulating BRCA1 protein stability and function in breast cancer.
Keywords
BRCA1, TUSC4, NPRL2, tumor suppressor, homologous recombination (HR) repair, protein stability, Breast Cancer