Arnold J. Levine, PhD

2009-2010 BCRF Projects:

1) Dr. Levine 's laboratory has identified four p53 regulated gene functions that play a critical role in breast cancers and regulate the functions of a signal transduction pathway (PI3K/AKT/mTOR) that responds to nutrient and stress signaling. In addition, a new p53 regulated gene has been identified, glutaminase-2, whose protein is localized in the mitochondria, enhances oxidative phosphorylation and is lost in some cancers altering metabolic pathways. This research has identified two new possible tumor suppressor genes (glutaminase-2, AMP kinase) whose loss from cancer cells contribute to the breast cancer phenotypes.

Over the past years the Levine team been able to identify a long list of genes that when mutated contribute to the origins of cancers in humans. These genes fall into two classes: tumor suppressor genes that help prevent cancer, and oncogenes that promote cancer. These genes were assembled into functional networks that carry out critical functions in a cell and in the body such as monitoring responses to nutrients, stress, hormonal changes, exposures to mutagens or carcinogens etc. This research has begun to demonstrate how these networks interact and regulate each other. The scientists have demonstrated at the genetic level how tumor suppressor genes in the p53 stress response pathway turn off the pathways that determine growth and division of cells in times of stress so as to prevent a high mutation rate and the formation of cancers. This research has uncovered two new candidates for tumor suppressor genes both of which respond to nutrient levels and modulate the production of energy in a cell. They are an integral part of our understanding and relating nutrition and the genes that cause cancers.

Mid-Year Progress Report:
The goals of this proposal are to translate the observations about the genetic predispositions and environmental risks of the patients with breast cancer so as to understand these causal variables at the cellular and molecular levels. In this way scientists can design options for prevention and drugs for treatment of breast cancers. Among the environmental risk factors are age, number of pregnancies, exposure to hormones, obesity, diet and nutritional status.

These past and present experiences interact with genetic factors resulting in a risk profile. In this research, Dr. Levine’s group has uncovered and connected molecular pathways that respond to diet, hormonal regulation, obesity (fat cells) and body mass and connected these functions with the patients response to stress signals. A tumor suppressor gene called p53 responds to stresses and shuts down the growth and division processes regulated by the insulin like growth factor pathway. These same networks in laboratory models influence longevity and the disease-free aging process. The researchers have transferred genetic material from a human into models so that the models now respond to stress signals very much like humans and develop breast cancers. This provides the opportunity to test environmental influences upon genetic polymorphisms in the p53 pathway.

2) The Regina Quick Award
Co-Investigator: Kim Hirshfield, MD, 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 and the risk of recurrence. Genetic variations in a set of genes, termed the p53 pathway genes, deal with our ability to respond to stress such as chromosome damage, nutritional depravation, heat or cold shock and the exposure to chemical mutagens and carcinogens. The goal of this research is to identify women at higher risk for developing breast cancers at young ages so they may begin more intensive screening to detect such cancers at an early stage. In addition, the researchers are uncovering risk factors for relapse after cancer treatment so that these women may be either treated differently or followed more closely. They have surveyed 142 genes in the p53 pathway for evidence of alleles that are under positive or negative selection over recent evolutionary time frames. Of those, they have identified eight single nucleotide polymorphisms in eight genes that appear to have a functional activity that is under selection pressure. Of these, five SNPs impact upon an early developmental stage in human embryos and two SNPs have demonstrated reproducible evidence of increasing the incidence and lowering the age of onset of breast cancers in humans.

Mid-Year Progress Report:
Drs. Levine and Hirshfield have identified polymorphisms in two genes that regulate the levels and activity of a tumor suppressor gene, p53, in preventing breast cancers from arising in women. These polymorphisms lower the age of onset and increase the frequency of different kinds of breast cancers. They have been able to reproduce this observation in a laboratory model that develops breast cancers which now permits the researchers to explore environmental variables, estrogen levels and other factors that might impact upon tumor development. In addition they have uncovered a potential polymorphism in parents that may transmit higher error rates, polymorphisms or copy number variations of genes (CNVs), to their children. They are testing the possibility that one of these CNVs plays a role in the inherited basis of breast cancers.

Bio:
Arnold Levine's research centers on the causes of cancer. In 1979, Levine and others discovered the p53 tumor suppressor protein, a molecule that inhibits tumor development. As chair of the National Institutes of Health Commission on AIDS Research and the National Academies Cancer Policy Board, he has helped determine national research priorities. He established the Institute's Center for Systems Biology, which concentrates on research at the interface of molecular biology and the physical sciences; on genetics and genomics, polymorphisms and molecular aspects of evolution, signal transduction pathways and networks, stress responses, and pharmacogenomics in cancer biology.

PhD, University of Pennsylvania, 1966; Postdoctoral Fellow, California Institute of Technology, 1966-68; Professor, Princeton University, 1968-79; Professor, State University of New York, Stony Brook, School of Medicine, 1979-84; Harry C. Wiess Professor, Princeton University, 1984-88, Chair, Department of Molecular Biology, 1984-96; President and Chief Executive Officer, Rockefeller University, 1998-02, Heilbrunn Professor of Cancer Biology, 1998-02; Visiting Professor, Institute for Advanced Study, 2002-04, Professor, 2004-; Medal for Outstanding Contributions to Biomedical Research, Memorial Sloan-Kettering Cancer Center, 2000; Keio Medical Science Prize, Keio University Medical Science Fund, 2000; Albany Medical Center Prize, 2001; Award for Basic Research, Surgical Society of Oncologists, 2003