J. Dirk Iglehart, MD

2013-2013 BCRF Project:
(made possible by generous support from Price Chopper Supermarkets/Golub Corporation)
Co-Investigators: Andrea Richardson, MD and Zhigang Charles Wang, MD, Brigham and Women's Hospital, Harvard Medical School, Boston

In 2012, this research group published several articles on their studies funded by The Breast Cancer Research Foundation. In the Cancer Research journal, Drs. Iglehart, Richardson, and Wang reported that LAPTM4B promotes cell survival during stress and faster tumor growth by inducing autophagy, a scavenger-like process allowing tumor cells to conserve nutrients when external nutrient supply is low. They found that knocking down expression of LAPTM4B reduces tumor growth in a laboratory tumor model.

Also, they published in the Cancer Discovery journal their work reporting that triple negative breast cancers that carry a high level of chromosome rearrangement resulting from improperly repaired DNA strand breaks are more sensitive to cisplatin treatment. They have recently found that overexpression of two genes, BLM and FANCI, is also associated with cisplatin sensitivity and reducing expression of these genes makes tumors more resistant to cisplatin. In addition, this team has continued work on altered expression of microRNAs (regulatory RNA molecules). They reported their results on microRNA expression profiling of breast cancers in a poster at the 2011 San Antonio Breast Cancer Symposium where they found that the miR-17-92 cluster as significantly overexpressed in triple negative breast cancers and that these tumors may be addicted to high miR17-92 for cell survival. Furthermore, these researchers have recently identified miR-218 as a potential regulator of BRCA1. In 2012-2013, this group will continue the projects described above as well as continue to participate in the cisplatin trial jointly conducted among several BCRF-funded teams at Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, and University of Pennsylvania Abramson Family Cancer Center.

Mid-year Progress: The research team at the Brigham and Women's Hospital and Dana-Farber Cancer Institute is a cross-discipline collaboration of a surgeonl oncologist and two pathologists who are both PhD-level human geneticists. This team has been continuously funded by BCRF for ten years. They have published and presented work that receives international attention and brings credit to the Foundation.

This year, the Brigham team reports progress in three areas. In the first project, they extend their discovery of a genetic change seen in 20% or 30% of breast cancers. There is good reason to believe a common drug used in humans for treatment of malaria targets is able to target the molecular consequences of the genetic change and can add benefit when combined with standard breast cancer therapy. In the second project, the team continues to pursue the consequences of a regulatory system called "micro RNAs" in the genesis and behavior of breast cancer. Finally, the group works on determining the consequences of the loss of facility in the repair of DNA in cancer. As a result of faulty DNA repair, instability of the cancer genome ensues, which is a double-edged sword from the patient's perspective. On the one hand, mutations that cause cancer and produce treatment resistance increase. On the other hand, the inability to repair damaged DNA can lead to increased sensitivity to certain treatments that target cancer DNA. A short-hand test for instability was devised and the right to deploy this test has been licensed by a large genetic diagnostic company. The Brigham team continues its focus on the genetics of breast cancer and continues to publish and present work supported by the Foundation. Where possible, discoveries are being translated into practice by this BCRF team.

Bio:
Dirk Iglehart is Anne E. Dyson Professor of Women's Cancers and Surgery, at Brigham and Women's Hospital/Dana-Farber Cancer Institute. After graduation from Harvard Medical School, he 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 National Cancer Institute program project grants which emphasize translational or bench-to-bedside research.