Molecular Genetics of Breast Cancer
We have performed a genome wide search for genes involved in breast cancer by SAGE and microarray. We are currently analyzing potential oncogenes and tumor suppressor genes which were idendified by this analysis. These genes include a tight junction protein, claudin-7, cell cycle regulators, cyclin D2 and 14.3.3 sigma, an epithelial apical surface protein, SPR1, and the hemotic gene, HOXA5. HOXA5 behaves as a tumor suppressor protein in breast epithelial cells, possible through its potent transcriptional regulation of the progesterone receptor and of p53 expression and apoptosis. Developmental abnormalities in HOXA5 minus mice are currently being investigated. Gene profiling using a common mammachip is being conducted to prepare a roadmap of molecular changes that occur during cancer progression from atypical hyperplasia to cancer. Another goal of the laborabory is to develop molecular markers for detection of cancer cells in biological fluids. We are currently studying a panel of methylated genes as a cancer screening marker in breast ductal lavage fluid and blood of breast cancer patients. On another front, we are attempting a radical approach to breast cancer prevention and therapy. This consists of introducing cytotoxic agenst through the mammary duct, using a variety of viral vectors to achieve selective ablation of breast epithelial cells and microtumors.
Nacht, M., Ferguson, A.T., Zhang, W., Petroziello, J.M., Cook, B.P., Gao, Y.H., Maguire, S., Riley, D., Coppola, G., Landes, G.M., Madden, S.L. and Sukumar, S., Combining SAGE and array technologies to identify genes differentially expressed in breast cancer, Cancer Res., 59: 5464-70, 1999.
Ferfuson, A.T., Evron, E., Umbricht, C.B., Pandita, T.K., Chan, T.A., Hermeking, H., Marks, J., Lambers, A., Futreal, A.P., Stampfer, M.R., and Sukumar, S., High frequency of hypermethylation at the 14-3-3 σ locus leads to gene silencing in breast cancer, PNAS, 97: 6049-6054, 2000.
Raman, V., Martenson, S.A., Reisman, D., Marks, J., Jaffee, E., and Sukumar, S., Control of p53 transcription by HOXA5: role in breast cancer, Nature, 405: 975-978, 2000.
Raman, V., Tamori, A., Vali, M., Zeller, H., Korz, D., and Sukumar, S., HOXA5 regulates expression of the progesterone receptor, J. Biol. Chem., 34: 26551-26555, 2000