J. Dirk Iglehart, MD

2007-2008 BCRF Project:
Co-Investigator: Andrea Richardson, MD, Brigham and Women's Hospital, Harvard Medical School, Boston

BCRF supports a multidisciplinary team consisting of a pathologist, clinician and geneticist who together work on the genetics of breast cancer. This team has delineated the molecular diversity of breast cancer and major trends in the genetics of the disease. This year, they will focus on chromosome 8 and genes that contribute to breast cancer cause, metastasis and treatment resistance.

Last year, the investigators at the Brigham and Women's Hospital examined two genes and their protein products in more depth, using experimental systems in the laboratory and in laboratory models. While the whole region provides a poor prognosis, individual genes appear to carry out special deleterious functions in metastasis and resistance to certain chemotherapy. They will pursue these findings further in the year to come. BCRF started this work several years ago as an exploratory project, the scientists narrowed their focus to chromosome 8, and now are ready to tackle individual genes and reduce this research to practice by developing biomarkers and even treatment interventions.

Mid-Year Progress Report:
The group at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute has uncovered a region of chromosome 8 that is over-represented in breast cancer cells compared to normal tissues, which contain two copies of this and all other regions. This over-representation is called "gene amplification". The Boston team has completed its investigation of the effect of having gene amplification on chromosome 8, and is analyzing the most likely genes that are increased in number and activity. These studies will be communicated to the scientific community in a manuscript, to be submitted for publication early in 2008.

Patients whose tumors contain gene amplification on chromosome 8 are prone to early disease recurrence, disease metastasis and resistance to commonly used chemotherapy. The researchers believe individual genes on the amplified region of the chromosome explain each of these effects: poor prognosis, metastasis and drug resistance. They have investigated the later (drug resistance) in more detail. One gene, called Lysosome Associated Protein Trans-Membrane 4B (LAPTM4B), appears to mediate resistance to a commonly used drug, doxorubicin (Adriamycin).

This research has uncovered the reason for the resistance, and it turns out to be novel and somewhat unexpected. Elevated levels of LAPTM4B direct the retention of doxorubicin in the cell lysosome (a cell "waste-basket" that targets its contents for extrusion or inactivation). Reducing LAPTM4B levels results in the rapid accumulation of doxorubicin in the cell nucleus, and the rapid appearance of cytotoxic effects on the tumor genome.

Future research, supported by the Foundation, will examine ways to inhibit the action of LAPTM4B. In addition, other functions of chromosome 8 genes remain to be uncovered, including how these genes cause cancer and promote its metastasis.

Bio:
Dirk Iglehart graduated from Harvard Medical School and went on to do his surgical residency at Duke University Medical Center in Durham, North Carolina. In 1999, he was recruited to Harvard Medical School where he maintains both an active clinical practice as well as a laboratory which studies the fundamental issues of breast cancer. In October of 2000, Dr. Iglehart became the Director of the Dana-Farber / Harvard Specialized Program of Research Excellence (SPORE) in breast cancer. SPOREs are large NCI program project grants which emphasize translational or bench-to-bedside research.