Project:
Window Trials of Histone Deacetylase Inhibitor (HDACi) Therapy for DCIS

Principal Investigator - E. Shelley Hwang, MD, MPH

ABSTRACT

Scientists have long recognized that genetic abnormalities play a central role in cancer development. However, important discoveries made in the last decade have confirmed that some cellular molecular changes, while not directly causing genetic mutations, can nevertheless bring about abnormal gene expression. These cellular changes are called "epigenomic" alterations, and one of the primary ways in which an epigenomic mechanism can exert its effect is through the modification of histone proteins. Histones are the "spools" around which the DNA of a cell is tightly wound. A family of proteins, named histone deacetylases, can remove the acetyl molecules, which are placed at specific sites of the histone proteins, causing abnormal folding of targeted regions of DNA, and thus alter gene expression at those sites. A new class of drugs called the histone deacetylase inhibitors, or HDAC inhibitors, exploits this finding by blocking the removal of acetyl molecules, effectively preventing abnormal gene expression. In cell culture and animal studies, this strategy has been shown to slow growth of cancer cells, and one such drug, suberoylanilide hydroxamic acid (SAHA) has been approved by the FDA for the treatment of lymphoma. HDAC inhibition of breast cancer cells is an exciting area of active research. Preliminary work in our lab has shown that the greatest reduction in acetylation occurs during the transformation between normal cells to preinvasive breast cancer, or DCIS. The goal of this proposal is to build upon this observation, and to determine whether women with DCIS treated with a short course of SAHA show a reversal in deacetylation, and whether these molecular alterations are accompanied by any measurable change in those pathways important for cancer growth and survival. Such findings would have important implications for cancer progression and may also indicate a future role for HDAC inhibitors in breast cancer prevention.