J. Dirk Iglehart, MD

2009-2010 BCRF Project:
(made possible by generous support from Price Chopper)
Co-Investigator: Andrea Richardson, MD, Brigham and Women's Hospital, Harvard Medical School, Boston

In the past year, investigators at the Brigham and Women's Hospital and Dana-Farber Cancer Institute have demonstrated that tumor expression levels of two 8q22 amplified genes were highly predictive of resistance to anthracycline chemotherapy in a recently completed neoadjuvant trial of epirubicin monotherapy in ER-negative breast cancers, but were not predictive of response to cisplatin chemotherapy. In vitro experiments show that the effects of these genes on drug resistance may be mediated in part through suppression of tumor cell death (apoptosis) and autophagy. In another avenue of work, the researchers found that degree of chromosomal instability in triple-negative breast tumors as measured by number of chromosomal breakpoints is highly associated with sensitivity to the DNA-damaging agent, cisplatin. Their findings this year on prediction of response to anthracyclines or cisplatin chemotherapies suggest a possible future approach to selection of optimal therapy for personalized treatment of breast cancer.

This year, in collaboration with investigators at MIT/Whitehead Institute, the Dana Farber/Brigham & Women's researchers identified an important and here-to-fore unrecognized metastasis-promoting alteration in certain human breast cancers. This alteration is the loss of microRNA-31, a metastasis suppressor. MicroRNAs do not code for proteins themselves, but are master regulators of the expression of panels of genes, thereby controlling key biological processes. In basic science work done by Dr. Robert Weinberg (also supported by BCRF), it was determined that miR31 is a microRNA that controls genes involved in cell invasion, adhesion, and survival. When miR31-control is lost, the tumor cell gains the ability to survive and metastasize to distant sites.

This will be the first translation of that basic work into the clinical realm and the observations made will be quite novel. In a pilot study, the group at Dana-Farber found that loss of miR31 in primary breast tumors was highly associated with metastatic recurrence, independent of other prognostic factors such as tumor grade or subtype. In this application, the group will validate miR31 as a predictor of metastatic recurrence in a larger cohort of primary breast cancers and will also investigate whether miR31 expression changes/decreases as tumors progress from growing in the breast to growing in distant sites. In related work, the Dana-Farber team will investigate the role of microRNAs in controlling genetic instability and response to chemotherapy in triple negative breast cancer.

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 NCI program project grants which emphasize translational or bench-to-bedside research.