Research Summary
I serve as the Director of the Breast Cancer Program in the Dana-Farber/Harvard Cancer Center (DF/HCC) and I am Principal Investigator of the Specialized Program of Research Excellence (SPORE) in Breast Cancer at Harvard. At the Brigham, I am attempting to organize a Section of Cancer Biology in the Division of Surgical Oncology to bring cancer researchers in the Division together. At the Dana-Farber, I am the Director of the Women’s Cancers Program (WCP). The WCP serves as a catalyst for clinical and basic research in breast and gynecologic cancers by raising foundation and private funds, and distributing these funds to support cancer research and education within the Dana-Farber and Brigham and Women’s Hospital. As an example of the educational mission, we sponsor two annual research symposia, on breast and ovarian cancer, for the DF/HCC. These symposia are attended by 200 or more researchers, feature poster presentations, oral presentations, and a published abstract book. As an example of fostering research, the WCP has regular RFA announcements for research in breast and GYN cancers.
My laboratory, like my research, is not typical. I have encouraged junior faculty members to associate together, under the umbrella of the Women’s Cancers Program. The idea was to create an interactive and multidisciplinary laboratory that focuses on translational research.
NF-kB Signaling
NF-kB is a master controller of cell fates, including proliferation and avoidance of apoptosis. Deb Biswas found activated NF-kB in specific subtypes of breast cancer, predominantly activated in ER-negative disease. In fact, ER-positive cancer is distinguished by very diminished NF-kB activity. In HER2-positive cancer cells, NF-kB activation is required for HER2-mediated proliferation and inhibiting NF-kB signaling causes growth arrest and apoptosis. In progressively growing xenografts, interruption of NF-kB prevents tumor outgrowth. We hypothesize that NF-kB inhibition will add or synergize with HER2-directed therapies (e.g., trastuzumab and lapatinib), and NF-kB activation may be a route to therapy resistance. Model systems are being constructed to test these ideas. In parallel work, Dr. Aundrea Oliver from the Department of Surgery observed activation of the normally quiescent NF-kB pathway in ER-positive breast cancer cells that acquire endocrine resistance. Clinical application awaits the development of NF-kB-specific drugs, which are not currently available. The only approved drug is bortezomib (Velcade), a proteosome inhibitor that prevents degradation of IkB (the cytoplasmic inhibitor of NF-kB). However, the NF-kB pathway provides numerous places for more specific inhibitors, and future work may focus on small molecule inhibitors of the pathway.
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Funding
1. Sundry (PI: Iglehart, 12/2005 - 12/2010)
2. Sundry (PI: Iglehart, 01/2000 - 09/2009) -- “The Eugene and Janet Salem Res Fellow in Surgical Oncology”
3. NIH-NCI T32 (PI: Iglehart, 09/2004 - 08/2009) -- “Advanced Training in Surgical Oncology”
4. Breast Cancer Research Foundation (PI: Iglehart, 10/2005 - 09/2008) -- “Integrated Genomics to Explore Breast Cancer Metastasis”
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