Professor of Surgery
UNC Breast Center
Area of interest
We previously developed a model of the angiogenic switch by sequential introductions of simian virus 40(SV40) large T (tumor) antigen and H-ras into murine endothelial cells. When endothelial cells expressing the SV40 large T antigen were injected into mice, they formed hemangiomas with low proliferative and apoptotic indices and had low production of VEGF. Whe H-ras was introduced into these cells, they formed rapidly proliferating angiosarcomas in vivo, and had high VEGF-production levels. This study demonstrated that introduction of a single gene resulted in a switch to the angiogenic phenotype and broke tumor dormancy.
We have recently shown, using immunohistochemistry, that breast cancer micrometastases (obtained from sentinel lymph nodes) have lower proliferation rates, decreased angiogenesis, and no difference in apoptosis, when compared to macroscopic axillary lymph node metastases (obtained from patients with greater than 15 positive axillary nodes). In the current proposal we will take two approaches to characterize the molecular profiles of micrometastases.
The first approach is hypothesis driven: Since immunohistochemistry has shown us that breast cancer micrometastases have decreased proliferation and angiogenesis, we hypothesize that there will be a difference in expression of genes involved in angiogenesis and cell-cycle regulation. We will therefore use laser capture microdissection, amplification, and RT-PCR to look for differences in expression of important genes known to be related to angiogenesis (VEGF, b-FGF, angioprotein, thrombospondin, matrix metalloprotteinases, and TGF-beta) and cell cycle regulaiton (P53, H-RAS, cyclin D1, and c-myc).
The second approach is an inductive approach to look for genes we might not anticipate, or that might not be previously characterized. This approach will use laser capture microdissection of lymph node micro- and macrometastases, amplificaiton, and tumor genetic profiling using cDNA microarrays. This second approach, although risky, is innovative with a potential high impact for discovering new paradigms. The genetic regulation of human micrometastases is not known, and this would be the first characterization of human micrometastases of its sort.
This current research will elucidate whether differences in biologic outcome between patients with micrometastic disease versus macrometastatic disease can be explained by differences in gene expression. Understanding the biological mechanisms of micrometastases will contribute significantly to the design of treatment strategies for patients with micrometastatic disease.
Awards and Honors
- 2004 Department of Defense Physician-Scientist Training Award for Breast Cancer Research
- 2003 NIH BIRWCH Scholar Award
- 2003 The Kimmel Scholar Award for Translational Research
- 2002 American Society of Clinical Oncology, The Breast Cancer Research Foundation Clinical Research Career Development Award
- 2000 Society of Surgical Oncology/ Aztrazeneca Oncology Fellowship Award for Clinical Research