Kim Hirshfield, MD, PhD

2012-2013 BCRF Project:
Co-Investigator: Arnold J. Levine, PhD, The Institute for Advanced Study, Princeton, and the Cancer Institute of New Jersey, New Brunswick, NJ

Genetic variations between individuals can confer a risk for the development of breast cancer, the age of onset of a breast cancer, the response to treatment for a breast cancer and the risk of developing a re-occurrence of a breast cancer. Drs. Levine and Hirshfield have identified three genes, ZNF585B, ZNF709, and ZNF788, which are expressed in normal breast tissue but are not in many breast cancers. When the ZNF genes are turned off, there is an increased level in the expression of two different human endogenous retroviruses in the cancer cells. These retroviruses insert their DNAs into the host genome and can cause mutations that activate oncogenes and inactivate tumor suppressor genes. As such, these zinc finger genes are candidates for new breast cancer tumor suppressor genes. Drs. Levine and Hirshfield will test this hypothesis.

Mid-year Progress: Examining the polymorphisms in the p53, p63 ands p73 pathways in humans has uncovered a new class of oncogenes involved in triple negative breast cancers. Drs. Hirshfield and Levine have identified a gene fusion copy number polymorphism present in 25% of the Western Caucasian population that appears to be transcriptionally silent in normal tissue but expressed in triple negative breast cancers. The extra copy gene fusion is composed of a fusion of the KANSL-1 gene and the ARL17A gene. KANSL-1 is part of a histone acetyltransferase found in the MLL, NSL and MSL complexes that acetylate and regulate H-4 histones as well as the p53 and ATM proteins. When the c-DNA from this fusion gene that is expressed in triple negative breast cancers is expressed in cell culture it inhibits the acetylation of histones and alters transcription of many genes. It also inhibits p53 activity, which responds to DNA damage and genomic instability by the killing these cancer cells. The fusion protein blocks ATM activity involved in DNA repair processes. The inhibition of these activities helps to explain why triple negative cancers have genomic instability. These results suggest two sets of drugs (HDAC inhibitors and PARP inhibitors) could be a useful treatment of those cancers with the KAMSL-1-ARL17A fusion gene containing tumors and we are testing these ideas in cell culture. A polymorphism in the PERP gene, which mediates p53-induced apoptosis, has been shown to be associated with recurrence free survival in women who have had both surgery and radiation treatment.

Bio:
Kim M. Hirshfield obtained her B.S. from Rutgers University and her Ph.D. in Biology with distinction in Biochemistry from Johns Hopkins University. She received her M.D. and completed residency in Internal Medicine and fellowship in Medical Oncology at UMDNJ/Robert Wood Johnson Medical School. Her medical training was followed by a post-doctoral fellowship with Dr. Arnold J. Levine at The Cancer Institute of New Jersey. Dr. Hirshfield is now an Assistant Professor in the Department of Medicine, Division of Medical Oncology at UMDNJ/Robert Wood Johnson Medical School where she specializes in early stage breast cancer and pre-malignant breast abnormalities at The Cancer Institute of New Jersey.

Dr. Hirshfield has an ongoing clinical trial to explore genetic determinants of breast cancer while also building a clinical database and sample repository at The Cancer Institute of New Jersey. Her specific research interest focuses on single nucleotide polymorphisms in genes of the p53 pathway and their contribution to clinical parameters such as risk, age of onset of breast cancer, and recurrence. Several polymorphisms are under study, especially as they play a role in hormone responsive breast cancers. Further laboratory work is aimed at elucidating the molecular mechanism behind these clinical findings.