Date of Graduation
12-2013
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Mien-Chie Hung Ph.D.
Committee Member
Dihua Yu M.D., Ph.D.
Committee Member
Elsa Flores Ph.D
Committee Member
Min Gyu Lee Ph.D.
Committee Member
Jonathan Kurie M.D.
Abstract
Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PRC2) and catalyzes the trimethylation of histone H3 on lysine 27 (H3K27Me3), to repress gene transcription. Many types of cancer stem and progenitor cells, including breast, have demonstrated EZH2 to be fundamental in the biology and promoting the expansion of their cellular populations. How EZH2 regulates each of these respective tumor initiating cells (TICs) populations has been studied, but the signaling transduction mechanisms that regulate EZH2 in these TIC populations is yet to be elucidated. Phosphorylation of EZH2 by cyclin dependent kinases (CDK) has been reported to control EZH2 epigenetic function and thus consequently control cancer cell proliferation, invasion, and stem cell differentiation. Our group has established that EZH2 and cyclin E, the enzymatic activator of CDK2, co-expresses with clinical significance in patient biopsies of triple-negative breast cancer (TNBC) compared to normal breast cancer. Thereafter we demonstrated CDK2 phosphorylates EZH2 endogenously on residue T416 in breast cancer cell lines in a cell cycle-dependent manner. EZH2-T416 phosphorylation (pT416) enhances the ability of EZH2 to increase cell migration/invasion, mammosphere formation, and in vivo tumor growth. Tumor growth and mammosphere formation are both mitigated with administration of CDK2 clinical trial inhibitor SNS032. Moreover, EZH2-T416 phosphorylation (pT416) correlates with poor patient survival specifically in TNBC patient biopsies, therefore paralleling the EZH2/cyclin E IHC staining previously observed in TNBC biopsy cohorts. We postulate pT416 to be a biomarker for aggressive forms of breast cancer, including TNBC and propose CDK2 inhibitor based therapy as a potential regimen for reducing the size of the breast cancer stem cell population and coordinately tumor size.
Keywords
EZH2, CDK2, breast cancer