Thesis Title

Ribosomal Targets of HDAC Inhibition in Breast Cancer

Graduation Date

Spring 2010

Document Type

Master's Thesis

Degree Name

Master of Science

Program Name

Biological Science

Program Director

Kiowa Bower, PhD

First Reader

Christopher Benz, MD

Abstract

ERBB2-positive breast cancer comprises about 25% of invasive breast cancers and is correlated with a poor clinical response and resistance to current treatments. As an alternative to current resistance-associated treatments, histone deacetylase (HDAC) inhibitors are being tested in clinical trials against various cancers, including breast cancer, and have shown potent antitumor activity. The mechanism behind this antitumor activity is largely unknown. In a recent study [1], pan-HDAC inhibitors like trichostatin-A (TSA) were demonstrated to initiate rapid degradation of ERBB2 mRNA transcripts and significantly inhibit viability of ERBB2-positive breast cancer cells. Additionally, it was demonstrated that these HDAC inhibitors induced ERBB2 mRNA degradation while the ERBB2 transcripts were polyribosome-associated. These studies generated the hypothesis that proteins associated with the polyribosome complex can regulate the degradation of ERBB2 and a number of other oncogenic transcripts, and that HDAC inhibitors likely activate one or more unknown mRNA-degrading proteins. Here we show, using 2D gel methodologies, that specific polyribosome-associated proteins such as RACK1 are post- translationally altered by TSA treatment and are thus candidates for promoting selective degradation of oncogenic transcripts like ERBB2. Such polyribosome- associated proteins could be exploited for future breast cancer therapeutics. While ribosomal proteins like RACK1 have been implicated in various cancers, nothing is known about their oncogenic function or role in the regulation of mRNA stability, particularly in response to HDAC inhibitor therapy. Altogether, this study shows that the modification of specific ribosomal proteins by a pan-HDAC inhibitor is a possible cytoplasmic mechanism mediating the antitumor effects of HDAC inhibitors in breast cancer.

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