The Estée Lauder Companies Brands Award in Memory of Evelyn H. Lauder
Kim Hirshfield, MD, PhD
Department of Medicine
UMDNJ/Robert Wood Johnson Medical School
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey
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 upon a person 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 reoccurrence of a breast cancer. Employing the Framingham Study containing three generation of individuals and thousands of families, Drs. Levine and Hirshfield have identified single nucleotide polymorphisms in the p73 and MRE-11 genes (which respond to DNA damage from environmental mutagens) that result in early onset breast cancers in the next generation. They have also identified a unique polymorphism in chromosome 17q21.3 encoding a fusion protein that behaves as an oncogene altering epigenetic marks and DNA damage responses. Their findings help to explain why some cancers have genomic instability and suggest that two sets of drugs (HDAC inhibitors and PARP inhibitors) could be a useful treatment of those cancers with the fusion protein expressed. They are testing these ideas in cell culture and their research focus in 2013-2014 will continue to pursue these lines of inquiry.
Changes at the DNA level of cells, known as genetic variations, are associated with increased risk of development of breast cancer and/or breast cancer outcomes. Drs. Hirshfield and Levine have identified a specific genetic variant found in about 25% of Caucasians. Their previous research showed that a specific gene variation results in a new gene product as a result of two cancer-causing genes (KANSL and ARL17A) being fused together. KANSL1 is part of a protein complex that regulates tumor suppression function and DNA repair proteins involved in cancer formation and cancer cell behavior. ARL17A is involved in movement of proteins within a cell and in turn, affects cell function.
When the two genes are combined, the resulting fusion gene presents itself as a genetic variation in the human genome in one quarter of Caucasian populations. In particular, the gene product was detected in 12 percent of breast cancers in this group. The new fusion gene’s impact on protein activity further sheds light on why some cancers – including breast – have difficulty maintaining the integrity of its DNA. As a result, two sets of drugs were identified that could be useful in the treatment of cancers with the fusion variation. The BCRF grant is supporting laboratory study of these agents and their impact on targeted therapy.
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.