Proteolytic Cleavage of ZNF217 Generates Small Proteins That Promote Breast Cancer Tumors and Metastasis to the Lung

Doctoral Dissertation
Thumbnail

Abstract

The transcription factor ZNF217 is amplified in 20-30% of breast cancers. Its overexpression accelerates tumor progression, metastasis, and chemoresistance in vivo and correlates strongly with poor prognosis in patients. Due to the high expression and heterogeneous localization of ZNF217 in some human breast tumors, both ZNF217 levels and localization may be critical determinants of ZNF217’s function. However, little is known about how ZNF217 is regulated as a protein to promote breast cancer. I discovered that breast tumors and cell lines express both full length and smaller ZNF217 proteins generated by a protease-dependent mechanism. Although the smaller ZNF217 proteins are even more prominent than full length ZNF217 in both human and mouse breast tumors and cell lines, the importance of these smaller forms remains unknown. To investigate the function of smaller ZNF217 proteins, I overexpressed ZNF217 truncation mutants in human breast cancer cells. Interestingly, removal of the N-terminus increased the cytoplasmic ZNF217 and significantly increased primary and metastatic tumor burdens in vivo. Calpain-induced proteolytic cleavage of ZNF217 protein to generate smaller proteins and increase cytoplasmic localization is a potential mechanism by which ZNF217 promotes oncogenic functions. Identification of the smaller ZNF217 oncoproteins as tumor promoting factors may be clinically valuable in generating an assay used to generate personalized treatment strategies for patients with advanced metastatic breast cancer and high ZNF217 expression.

Attributes

Attribute NameValues
Author Beth A. Facchine
Contributor Mary S. Stack, Committee Member
Contributor Holly V. Goodson, Committee Member
Contributor Laurie E. Littlepage, Research Director
Degree Level Doctoral Dissertation
Degree Discipline Chemistry and Biochemistry
Degree Name Doctor of Philosophy
Banner Code
  • PHD-BCHM

Defense Date
  • 2021-03-22

Submission Date 2021-04-19
Subject
  • Zinc Finger Transcription Factor

  • Breast Cancer

  • ZNF217

  • Proteolytic Cleavage

Record Visibility Public
Content License
  • All rights reserved

Departments and Units
Catalog Record

Files

Please Note: You may encounter a delay before a download begins. Large or infrequently accessed files can take several minutes to retrieve from our archival storage system.