David M. Livingston, MD

2009-2010 BCRF Project:
Basal-like breast cancer (BLC), sometimes referred to as triple-negative, is a major therapeutic problem, and this is all the more important an issue, because this particular subset of the disease represents a significant fraction (~15%) of all new breast cancers in the U.S. Dr. Livingston and colleagues have studied the function of one of the two, alternately spliced BRCA1 gene products (i.e. variant forms), IRIS. Although encoded by the BRCA1 gene, IRIS, a chromatin- associated protein, when overexpressed elicits cancerous behavior in otherwise normal mammary cells. It can, thus, behave like an oncogene rather than a tumor suppressor. These data, obtained in 78 sporadic primary human breast cancers, also reveal that IRIS, unlike the case in normal mammary cells, was markedly overexpressed in 28% of them. Specifically, 28% of these lesions contained > 5X more IRIS mRNA than a collection of normal mammary gland samples. It is also overexpressed in certain sporadic human breast cancer cell lines.

Furthermore, when experimentally overexpressed in primary mammary epithelial cells or spontaneously overexpressed in breast cancer lines, it actively elicited breast cancer progression properties, much like those observed during natural breast cancer formation. It does so, in part, by stimulating expression of the erbB2 protein, the target of Herceptin. These findings suggest that it operates as a therapeutic breast cancer target in those human tumors where it is spontaneously overexpressed. This hypothesis is now under active investigation.

IRIS is one of three, known BRCA1 gene products. There might be others, as yet undiscovered. Surprisingly, when overexpressed, it elicits in primary mammary cells a powerful cancerous effect, much like what is seen in naturally occurring human breast cancers. It is also overexpressed in certain sporadic human breast cancers, a setting where its hyperactive function likely contributes to cancer development. In such a setting, IRIS has earned the status of a potential cancer drug target, i.e. a protein whose ongoing function is necessary for tumor survival or progression. The Livingston team will test this hypothesis. If validated, they propose to initiate IRIS-directed drug discovery by screening for small molecules that specifically attack IRIS function in breast cancer cells.

Mid-Year Progress Report:
The BRCA1 gene encodes multiple protein products. One is p220, which elicits the state of cancer suppression that, when disturbed due to an inherited loss of p220 synthesis, triggers BRCA1 breast and ovarian cancer. The gene also encodes a protein called BRCA1�]IRIS (or IRIS). Recently, Dr, Livingston's group found that IRIS is, unlike p220, overexpressed in ~15% of sporadic breast cancers and can, in this setting, stimulate mammary epithelial cells to acquire malignant properties. Thus, although the product of a complex gene that is best known as a cancer-suppressing element, IRIS has cancer-stimulating properties that become apparent when it is spontaneously overexpressed in normal breast cells.

If this effect proves to be clinically relevant, the BRCA1 gene may contribute to both inherited (due to loss of p220 synthesis) and sporadic (abetted by IRIS overexpression) breast cancer. Unlike IRIS, p220 is concentrated in nuclear dot-like structures, especially after DNA damage (e.g. ionizing radiation, or x-ray exposure). The researchers have found that its concentration in these structures likely results, at least in part, in the suppression of one of its major DNA repair functions. Paradoxically, suppression of this p220 activity may well prevent cells from exhibiting the kinds of chromosomal abnormalities that are associated with tumor development.

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.