Professor, Pediatrics and Biochemistry
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey
Co-Investigator: Kim Hirshfield, MD, PhD, The Institute for Advanced Study, Princeton, and The Cancer Institute of New Jersey, New Brunswick, NJ
Dr. Levine is renowned for his work in establishing p53 as a tumor suppressor gene, one of the body's most important defenses against many forms of cancer. 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.
Project 1: 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.
Project 2: Dr. Levine’s team has tested the hypothesis that breast cancer stem cells arise efficiently in tumors with p53 mutations. Employing RNA micro arrays they showed that breast cancers with p53 mutations had stem cell signatures. Central to these signatures was the over-expression of two proteins MELK and TMEM97. The researchers have produced antibodies directed against these proteins and obtained cell lines that over-express these proteins and produce tumors in laboratory models. They are in the process of obtaining small molecule inhibitors of the MELK protein kinase and will be testing it and other derivatives to determine if MELK activity drives the growth of these tumors. Monoclonal antibodies directed against the cell surface protein TMEM97 are being prepared. This trans-membrane protein inserts cholesterol into the membrane of these cancer cells, and the Levine lab is testing whether or not the monoclonal antibodies inhibit tumor cell growth. The goal of this project is to develop novel potential therapeutic agents that inhibit or kill cells from triple negative and Her-2/neu breast cancers.
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.