Graduation Date

5-2018

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Meredith Protas, PhD

First Reader

Christopher Benz, MD

Second Reader

Kristylea Ojeda, PhD

Abstract

Breast cancer is the most common malignancy diagnosed in women. 15-20% of these cancers overexpress the HER2 (ERRB2) oncoprotein. HER2-positive breast cancers are generally aggressive and are associated with poor prognosis. Unfortunately, only a mere 30% of HER2-positve patients respond to therapies when they are used as a single agent. Combining therapeutics can potentially lead to synergy and improved anticancer efficacy, and there is clearly a need for the development of new HER2-directed therapeutics. Newer approaches include the utilization of histone deacetylase (HDAC) inhibitors. It has been observed that HDAC inhibitors can induce the rapid decay of oncogenic transcripts such as the HER2 mRNA, though the mechanism underlying this process remains undefined. Earlier observations in our lab led to speculation that protein(s) binding the 3’-untranslated region (UTR) of HER2 mRNA become acetylated following HDAC inhibitor treatment and promote the HER2 mRNA decay while engaged in the translational machinery. Pursuing this speculation, a key ribosome- or polyribosome-associated candidate suspected of interacting with and mediating this HER2 mRNA decay became a protein identified by mass spectrometry in cytosolic fractions containing rapidly degrading HER2 mRNA as a protein appearing hyper-acetylated within hours of breast cancer cell exposure to a pan-HDAC inhibitor. Studies conducted using pan-HDAC inhibitors like Trichostatin A (TSA) as well as various class-selective HDAC inhibitors, examine their comparative influences on the association of proteins with either the ribosome or polyribosome translational machinery, protein levels and acetylation status before and after HDACi treatment, and their functional impact on HER2 mRNA by modulating its expression levels. Understanding the mechanism by which optimal class-selective HDAC inhibitors modulate translation-associated proteins to facilitate HER2 mRNA degradation will allow for more effective use of HDAC inhibitor’s antitumor activity to combat HER2-positive breast cancers.

Available for download on Monday, August 02, 2021

Share

COinS