Stephen J. Weiss, MD

2012-2013 BCRF Project:
Dr. Weiss, who focuses on the mechanisms controlling cancer invasion and metastasis, with his laboratory team has uncovered a novel molecular network of interacting genes that control the behavior of almost all triple negative breast cancers. In this cascade, mutations in the p53 tumor suppressor gene (one of the most frequent mutations found in all cancer types) allow affected cells to increase their expression of Snail and Slug (two related genes that normally control the function of breast cells) to levels that impair normal cell function by down-regulating the DNA repair enzyme, BRCA1, while simultaneously up-regulating genes that control breast-cancer invasion and metastasis (i.e. the proteolytic enzymes MT1-MMP and MT2-MMP). These studies allow for the specific targeting of incorrectly regulated genes whose inhibition could lead to the development of new therapeutics for triple negative breast cancers.

Having identified a new molecular network that controls critical aspects of the behavior of triple negative breast cancers, Dr. Weiss's team now seeks to identify the individual genes that allow this pathway to regulate the growth, local invasion and metastatic behavior of triple negative breast cancer. Current evidence indicates that breast cancer cells may metastasize early in the disease process, but only to lay dormant in distant tissues. The molecular pathways that allow cancer cells to exit their dormant state and begin to grow anew are largely unknown. Dr. Weiss's current work is designed to determine the mechanisms that allow breast cancer cells to escape dormancy, how to prevent dormant cells from "awakening," and to prevent their progression should metastatic growth be re-engaged.

Mid-year Progress: Dr. Weiss's laboratory, which focuses on the mechanisms controlling cancer invasion and metastasis, has uncovered a novel molecular network of interacting genes that control the behavior of triple negative breast cancers. In this cascade, mutations in the p53 tumor suppressor gene (one of the most frequent mutations found in all cancer types) allow affected cells to increase their expression of Snail and Slug (two related genes that normally control the function of breast cells) to levels that impair normal cell function by down-regulating the DNA repair enzyme, BRCA1. In addition, the team has new evidence supporting that Snail and Slug control breast cancer growth by down-regulating a series of enzymes that normally act as "brakes" for controlling cell proliferation while playing an active role in driving new blood vessel formation (i.e. angiogenesis). They have also observed, at the same time, Snail and Slug up-regulate genes that control breast-cancer invasion and metastasis (i.e. the proteolytic enzymes MT1-MMP and MT2-MMP) as well as a cohort of new genes that regulate cancer stem cell function. Dr. Weiss hopes that these studies will allow for the specific targeting of incorrectly regulated genes whose inhibition could lead to the development of new therapeutics for triple negative breast cancers.

Bio:
After completing his BA, MD, and internship at Ohio State University and Washington University, Dr. Weiss was recruited to the Division of Hematology/Oncology at the University of Michigan in 1978. Most recently, Dr. Weiss served as the Division Chief of Molecular Medicine & Genetics and the Director of the Molecular Mechanisms of Disease Program at the University of Michigan. In 2006, he joined the Life Sciences Institute as a Research Professor.

Dr. Weiss' research efforts have long focused on the mechanisms used by cancer cells to remodel tissue structure during events ranging from inflammatory disease and angiogenesis to cancer. His highly cited works on the role of metalloproteinases in regulating these pathologic events have appeared consistently in top-ranked journals such as Science, Nature, Genes & Development, Journal of Cell Biology, Proceedings of the National Academy of Sciences, and Cell.

Dr. Weiss has received numerous honors and awards in the course of his academic career, including the National Young Investigator Award from the American Society for Clinical Research and a MERIT Award from the National Institutes of Health (NIH). He is a member of the American Society for Clinical Investigation, the Association of American Physicians, and in 2001 was selected as a member of the Institute of Medicine of the National Academy of Sciences. Dr. Weiss has also served on numerous committees at the NIH as well as the National Cancer Institute, and served as the Editor-in-Chief of Journal of Clinical Investigation from 1997 to 2002.