David M. Livingston, MD

2012-2013 BCRF Project:
Dr. Livingston's research focuses on the BRCA1 gene. Results from his laboratory showed for the first time that the product of the BRCA1 gene is engaged in a newly detected function - that is, suppression of the development of chronic DNA damage arising from unrepaired replication stress, which is known to increase an individual's likelihood of developing cancer. These researchers also made the surprising observation that BRCA1 DNA repair function operates under tight control afforded by an interaction between the protein and the RAP 80 complex. Based on laboratory observations, Dr. Livingston's team believes that too little or too much BRCA1 DNA repair function in cells predispose to chronic DNA damage and may lead to the development of cancer.

In 2012-2013, Dr. Livingston's team will focus on two projects. The first project aims to search for new insights into how BRCA1 mutations in otherwise normal mammary epithelial cells trigger the kinds of DNA damage that only occurs in proliferating cells and results in a progression to tumor development. The long-range goal of this research is to generate molecular insights that could become the basis for a mechanism‐driven BRCA1 cancer prevention strategy.

In project 2, Dr. Livingston's team will continue to dissect the detailed molecular connection between disorderly, unregulated IRIS function and metastasis development in those breast cancers that overproduce IRIS. This project is aimed at unearthing new molecular strategies for neutralizing IRIS function and, hence, for interfering with a major source of sporadic breast cancer metastasis formation.

Mid-year Progress: Dr. Livingston's laboratory is interested in how the BRCA1 breast cancer gene operates in humans and how its misbehavior triggers breast cancer. BRCA1 encodes multiple protein products, one of which, p220, performs the work of breast cancer prevention. How the other proteins operate has been a mystery. Recently, they found, for the first time, that one of the other BRCA1 proteins, an incompletely understood polypeptide named BRCA1-IRIS (aka IRIS), is widely overproduced in sporadic human breast cancer samples. In sporadic, non-hereditary breast cancers there is no known BRCA1 mutation, and BRCA1 function is intact. This finding hints at a possible role for IRIS overproduction in tumor development.

Surprisingly, Dr. Livingston's team also found that IRIS stimulates breast cancer metastasis in laboratory models of human breast cancer. In studying the mechanism that underlies this unexpected behavior, they now find that, when overexpressed, IRIS stimulates the biochemical system that allows cells to respond to and survive in lowered oxygen environments, a common property of tumor masses. Their latest results are consistent with a scenario in which this form of IRIS stimulation contributes to the IRIS-driven metastasis effect. If their ongoing and future work firmly supports this hypothesis, a specific means of interfering with this abnormal process already exists and will be tested as a new, experimental therapeutic strategy for sporadic, IRIS-overproducing breast cancer. This subtype represents approximately 25% of non-inherited human breast cancers. Non-inherited or sporadic breast cancers represent about 94% of all malignant breast tumors.

Bio:
Dr. Livingston received his A.B. from Harvard in 1961 and his M.D. from Tufts Medical School in 1965. He undertook his clinical training in internal medicine at Peter Bent Brigham Hospital and his scientific training at the NCI and at Harvard Medical School. He joined the Harvard faculty as Assistant Professor of Medicine in 1973 and has been a faculty member at HMS and at DFCI continuously since that time. He is now the Emil Frei Professor of Genetics and Medicine at HMS and DFCI, where he serves as Chair of the Executive Committee for Research; Director of The Charles A. Dana Division of Human Cancer Genetics; and Deputy Director of the Dana-Farber/Harvard Cancer Center.

Dr. Livingston served as Director and Physician-in-Chief at DFCI from 1991-1995 and Chair, Board of Scientific Advisors at the National Cancer Institute (1995-1999). He was elected to the Institute of Medicine of the National Academy of Sciences in 1990 and, in 1995, he was elected to the National Academy of Sciences. He is also a member of the American Academy of Arts and Sciences. In 1997, he received the Award for Distinguished Research in the Biomedical Sciences from the Association of American Medical Colleges and the Brinker International Award for Breast Cancer Research. In 2005, he received the Clowes Award for excellence in cancer research of the American Association for Cancer Research and the Theodor Boveri Award from the German Cancer Society.