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.

Mid-Year Progress Report:
Investigators at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital supported by this Breast Cancer Research Foundation grant have focused on the genetics of breast cancer as observed in malignancies obtained from women with the disease. Attempts are made to find recurring genetic alterations, relate these alterations to disease and treatment outcomes, and observe the changes during cancer progression.

This year, the group finished work on a region of genetic amplification (gene copy gain) on chromosome 8. The amplification is found in about one-in-five women with breast cancer, and when it occurs, is associated with a worse outcome despite treatment with chemotherapy. The region harbors genes that influence the response and defense of breast cancer to treatment, in particular to a commonly used class of drug known as anthracyclines. The work was published in January issue of Nature Medicine and acknowledges the critical support of BCRF. Through study of cells growing in the laboratory, further progress has been made in understanding how the genes from chromosome 8 support cancer cell growth and escape from death.

In addition, the Brigham and Dana-Farber team, in collaboration with other BCRF supported investigators (Garber, Tung, and Szallasi) has completed work on a neoadjuvant cisplatin mono-therapy treatment trial in triple negative breast cancers (TNBC). A subset of sporadic TNBC shares a profound sensitivity to the DNA damaging agent, cisplatin, similar to the BRCA1-associated tumors. Cisplatin-sensitive TNBC display reduced expression of BRCA1 RNA and protein and are more likely to harbor p53 truncating mutations. The findings were reported in the January issue of the Journal of Clinical Oncology and acknowledge BCRF support.

Additional studies completed this year analyzed chromosomal alterations in the TNBC tumors from the cisplatin treatment trial. This work was performed in collaboration with BCRF supported investigator, Zoltan Szallasi, and has highlighted the relationship between patterns of genome instability and cisplatin sensitivity. The TNBCs that carry a high level of chromosome rearrangement resulting from improperly repaired DNA strand breaks are more sensitive to cisplatin. A similar association was found in ovarian cancers treated with platinum drugs. Thus, levels of chromosome alterations measured in breast and ovarian tumor samples may provide an accurate biomarker for predicting tumor sensitivity to treatment with genotoxic agents. A manuscript has been prepared and submitted to the journal Nature Medicine. This year, the team at Dana-Farber is turning to examination of a new type of genomic alteration in breast cancers, altered expression of microRNAs. The initial preparation of samples has begun and microRNA expression profiling will commence shortly.

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.