Saraswati Sukumar, Ph.D.
Fax: (410) 614-4073
Interests:
- Breast Cancer Genes
Titles
Barbara B. Rubenstein Professorship in Oncology
Professor of Pathology
Professor, Johns Hopkins School of Nursing
Visiting Professor, The Oncology Research Institute, National University of Singapore
Schools/Degrees
M.S., Nagpur University, India Ph.D., Nagpur University, India
Training
Fellow, Molecular Biology, National Cancer Institute, NIH, Bethesda, MDResearch Summary
The research goal of the Sukumar laboratory is to obtain a molecular profile of breast cancer and to apply this knowledge to the early detection, diagnosis and therapy of breast cancer. Toward this end, SAGE, array, and proteomic analysis of breast carcinomas is being performed on noninvasive (ductal carcinoma in situ), invasive (invasive ductal carcinoma), and metastatic breast cancer (bone, ovarian, brain metastasis). The goal is to obtain mRNA and protein profiles of each cell type composing the lesion. This will help derive gene expression signatures typical for each stage of breast cancer for epithelial, stromal, and endothelial cells. By such careful analysis, candidate genes are identified, characterized and utilized for early detection and/or therapy of breast cancer.
Previous gene searches in breast cancer performed here identified a number of potential candidate tumor suppressors and oncogenes. These belonged to families of genes involved in a variety of functions in the cell. Transcription factors, such as HOXA5, WT1, RAR-beta and Twist; cell cycle regulators such as Cyclin D2 and 14.3.3 sigma; and tight junction proteins, such as Claudin-3, -4 and -7, were selected for further analysis. Biological analysis of these genes revealed molecular alterations that could lead to their aberrant function in breast cancer cells, results of which were published in the last three years. Hypermethylated promoter regions of a number of genes serve as tumor- specific markers for early detection of breast cancer. As described in a paper in Lancet in 2001, a marker panel consisting of Cyclin D2, RAR-beta and Twist was capable of detecting almost all breast cancers (96 percent) with a high level of specificity and sensitivity. This marker panel detected cancer in two high-risk women who were mammographically normal. This panel has now been improved by adding more markers, such as RASSF1A, HIN-1, ER-a and ER-b, and by developing a multiplex, quantitative methylation-specific PCR (Q-MSP). Q-MSP will allow accurate determination of the relative amount of methylation present in each gene, using less than nanogram amounts of DNA, in an objective manner. To test this premise, these markers are currently being applied to ductal cells obtained in two current trials aimed at validating the markers for early detection in high-risk women.
Soon, this panel will be tested as intermediate- response markers in a chemoprevention trial in collaboration with three other institutions in the United States. A combination of an objective test, such as MSP, with a subjective test, such as cytology, has the potential to provide an adjunct to mammography for early detection of breast cancer. This test is also being modified to detect tumor-specific DNA in serum from breast cancer patients.
The long-term goal is to provide a molecular blood test for early detection of breast cancer. Interrogating the hypothesis that breast cancer can be treated and prevented by delivery of agents via the intraductal route, both conventional and novel agents were tested. First, treatment of rats bearing carcinogen-induced tumors with Doxil results in complete regression of the tumors. Doxil administration via this route in a prevention setting, soon after carcinogen administration, also protected 90 percent of the treated glands. This mode of delivery can achieve therapeutic effects with less than one-third the systemic dose of the drug. This concept has also been tested in the HER2/neu mouse model for breast cancer. Here again, potent antitumor effects on established tumors were achieved by intraductal instillation of Doxil. Doxil also prevented the development of mammary tumors in this system. With the goal of eliminating the primary tumor and its metastasis, chemotherapy is being combined with immunotherapy (in collaboration with the Jaffee laboratory). Targeting genes that were found by our previous SAGE analysis searches to be overexpressed in breast cancer (the Claudins 3 and 4), we are testing therapies using Clostridium perfringens enterotoxin (CPE). CPE binds to the overexpressed tight junction proteins Claudin 3 and 4 on the tumor cells, resulting in tumor cell kill. No apparent cytotoxic effects are observed on normal epithelial cells. Additionally, the systemic toxic effects of CPE on the gastrointestinal tract are bypassed by utilizing the intraductal route of delivery. A combination of basic and preclinical research efforts in the laboratory aims at translating discoveries made at the bench to the clinic as rapidly as possible.
Journal Citations
Cao, D., Polyak, K., Halushka, M.K., Nassar, H., Kouprina, N., Iacobuzio-Donahue, C., Wu, X., Sukumar, S., Hicks, J., De Marzo, A., and Argani, P. (2008). Serial analysis of gene expression of lobular carcinoma in situ identifies down regulation of claudin 4 and overexpression of matrix metalloproteinase 9. Breast Cancer Res 10, R91.
Chen, H., H. Zhang, J. Lee, X. Liang, X. Wu, T. Zhu, P. K. Lo, X. Zhang, and S. Sukumar. 2007. HOXA5 acts directly downstream of retinoic acid receptor beta and contributes to retinoic acid-induced apoptosis and growth inhibition. Cancer Res 67:8007-13.
Chen, H., Lee, J.S., Liang, X., Zhang, H., Zhu, T., Zhang, Z., Taylor, M.E., Zahnow, C., Feigenbaum, L., Rein, A., and Sukumar, S. (2008). Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res 68, 3637-3644.
Davidson, N. E. & Sukumar, S. (2005). Of Snail, mice, and women. Cancer Cell 8, 173-4.
Fackler, M. J., Malone, K., Zhang, Z., Schilling, E., Garrett-Mayer, E., Swift-Scanlan, T., Lange, J., Nayar, R., Davidson, N. E., Khan, S. A. & Sukumar, S. (2006). Quantitative multiplex methylation-specific PCR analysis doubles detection of tumor cells in breast ductal fluid. Clin Cancer Res 12, 3306-10.
Gupta, A., Guerin-Peyrou, T.G., Sharma, G.G., Park, C., Agarwal, M., Ganju, R.K., Pandita, S., Choi, K., Sukumar, S., Pandita, R.K., Ludwig, T., and Pandita, T.K. (2008). The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis. Mol Cell Biol 28, 397-409.
Hallur, G., Jimeno, A., Dalrymple, S., Zhu, T., Jung, M. K., Hidalgo, M., Isaacs, J. T., Sukumar, S., Hamel, E. & Khan, S. R. (2006). Benzoylphenylurea sulfur analogues with potent antitumor activity. J Med Chem 49, 2357-60.
Han, L., P. D. Witmer, E. Casey, D. Valle, and S. Sukumar. 2007. DNA methylation regulates MicroRNA expression. Cancer Biol Ther 6:1284-8.
Huang, Y., Keen, J. C., Pledgie, A., Marton, L. J., Zhu, T., Sukumar, S., Park, B. H., Blair, B., Brenner, K., Casero, R. A., Jr. & Davidson, N. E. (2006). Polyamine analogues down-regulate estrogen receptor alpha expression in human breast cancer cells. J Biol Chem 281, 19055-63.
Huang, Y., Pledgie, A., Rubin, E., Marton, L. J., Woster, P. M., Sukumar, S., Casero, R. A., Jr. & Davidson, N. E. (2005). Role of p53/p21(Waf1/Cip1) in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells. Cancer Biol Ther 4, 1006-13.
Kominsky, S. L., B. Tyler, J. Sosnowski, K. Brady, M. Doucet, D. Nell, J. G. Smedley, 3rd, B. McClane, H. Brem, and S. Sukumar. 2007. Clostridium perfringens enterotoxin as a novel-targeted therapeutic for brain metastasis. Cancer research 67:7977-7982.
Lau, Q. C., Raja, E., Salto-Tellez, M., Liu, Q., Ito, K., Inoue, M., Putti, T. C., Loh, M., Ko, T. K., Huang, C., Bhalla, K. N., Zhu, T., Ito, Y. & Sukumar, S. (2006). RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 66, 6512-20.
Lee, J. S., P. K. Lo, M. J. Fackler, P. Argani, Z. Zhang, E. Garrett-Mayer, and S. Sukumar. 2007. A Comparative Study of Korean with Caucasian Breast Cancer Reveals Frequency of Methylation in Multiple Genes Correlates with Breast Cancer in Young, ER, PR-negative Breast Cancer in Korean Women. Cancer Biol Ther 6.
Lee, J.S., Fackler, M.J., Teo, W.W., Lee, J.H., Choi, C., Park, M.H., Yoon, J.H., Zhang, Z., Argani, P., and Sukumar, S. (2008). Quantitative promoter hypermethylation profiles of ductal carcinoma in situ in North American and Korean women: Potential applications for diagnosis. Cancer Biol Ther 7, 1398-1406.
Li, J., Zhao, J., Yu, X., Lange, J., Kuerer, H., Krishnamurthy, S., Schilling, E., Khan, S. A., Sukumar, S. & Chan, D. W. (2005). Identification of biomarkers for breast cancer in nipple aspiration and ductal lavage fluid. Clin Cancer Res 11, 8312-20.
Lo, P. K., Mehrotra, J., D'Costa, A., Fackler, M. J., Garrett-Mayer, E., Argani, P. & Sukumar, S. (2006). Epigenetic suppression of secreted frizzled related protein 1 (SFRP1) expression in human breast cancer. Cancer Biol Ther 5, 281-6.
Lo, P.K., and Sukumar, S. (2008). Epigenomics and breast cancer. Pharmacogenomics 9, 1879-1902.
Lodge, M.A., Jacene, H.A., Pili, R., and Wahl, R.L. (2008). Reproducibility of tumor blood flow quantification with 15O-water PET. J Nucl Med 49, 1620-1627.
Lorincz, A. M. & Sukumar, S. (2006). Molecular links between obesity and breast cancer. Endocr Relat Cancer 13, 279-92.
Mambo, E., Chatterjee, A., Xing, M., Tallini, G., Haugen, B. R., Yeung, S. C., Sukumar, S. & Sidransky, D. (2005). Tumor-specific changes in mtDNA content in human cancer. Int J Cancer 116, 920-4.
Mankoo, P.K., Sukumar, S., and Karchin, R. (2008). PIK3CA somatic mutations in breast cancer: Mechanistic insights from Langevin dynamics simulations. Proteins.
Marlow, R., Strickland, P., Lee, J.S., Wu, X., Pebenito, M., Binnewies, M., Le, E.K., Moran, A., Macias, H., Cardiff, R.D., Sukumar, S., and Hinck, L. (2008). SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium. Cancer Res 68, 7819-7827.
Mohankumar, K. M., X. Q. Xu, T. Zhu, N. Kannan, L. D. Miller, E. T. Liu, P. D. Gluckman, S. Sukumar, B. S. Emerald, and P. E. Lobie. 2007. HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells. Oncogene 26:3998-4008.
Murata, S., Kominsky, S. L., Vali, M., Zhang, Z., Garrett-Mayer, E., Korz, D., Huso, D., Baker, S. D., Barber, J., Jaffee, E., Reilly, R. T. & Sukumar, S. (2006). Ductal access for prevention and therapy of mammary tumors. Cancer Res 66, 638-45.
Rubin, E., X. Wu, T. Zhu, J. C. Cheung, H. Chen, A. Lorincz, R. K. Pandita, G. G. Sharma, H. C. Ha, J. Gasson, L. A. Hanakahi, T. K. Pandita, and S. Sukumar. 2007. A role for the HOXB7 homeodomain protein in DNA repair. Cancer Res 67:1527-35.
Shipitsin, M., L. L. Campbell, P. Argani, S. Weremowicz, N. Bloushtain-Qimron, J. Yao, T. Nikolskaya, T. Serebryiskaya, R. Beroukhim, M. Hu, M. K. Halushka, S. Sukumar, L. M. Parker, K. S. Anderson, L. N. Harris, J. E. Garber, A. L. Richardson, S. J. Schnitt, Y. Nikolsky, R. S. Gelman, and K. Polyak. 2007. Molecular definition of breast tumor heterogeneity. Cancer Cell 11:259-73.
Suijkerbuijk, K.P., Fackler, M.J., Sukumar, S., van Gils, C.H., van Laar, T., van der Wall, E., Vooijs, M., and van Diest, P.J. (2008). Methylation is less abundant in BRCA1-associated compared with sporadic breast cancer. Ann Oncol 19, 1870-1874.
Swift-Scanlan, T., Blackford, A., Argani, P., Sukumar, S. & Fackler, M. J. (2006). Two-color quantitative multiplex methylation-specific PCR. Biotechniques 40, 210-9.
Visvanathan, K., Sukumar, S. & Davidson, N. E. (2006). Epigenetic biomarkers and breast cancer: cause for optimism. Clin Cancer Res 12, 6591-3.
Winnard, P.T., Jr., and Sukumar, S. (2008). A PET rat model for assessing the effectiveness of new chemotherapies. Cancer Biol Ther 7, 538-539.
Wood, L. D., D. W. Parsons, S. Jones, J. Lin, T. Sjoblom, R. J. Leary, D. Shen, S. M. Boca, T. Barber, J. Ptak, N. Silliman, S. Szabo, Z. Dezso, V. Ustyanksky, T. Nikolskaya, Y. Nikolsky, R. Karchin, P. A. Wilson, J. S. Kaminker, Z. Zhang, R. Croshaw, J. Willis, D. Dawson, M. Shipitsin, J. K. Willson, S. Sukumar, K. Polyak, B. H. Park, C. L. Pethiyagoda, P. V. Pant, D. G. Ballinger, A. B. Sparks, J. Hartigan, D. R. Smith, E. Suh, N. Papadopoulos, P. Buckhaults, S. D. Markowitz, G. Parmigiani, K. W. Kinzler, V. E. Velculescu, and B. Vogelstein. 2007. The genomic landscapes of human breast and colorectal cancers. Science 318:1108-13.
Wu, G., Guo, Z., Chatterjee, A., Huang, X., Rubin, E., Wu, F., Mambo, E., Chang, X., Osada, M., Sook Kim, M., Moon, C., Califano, J. A., Ratovitski, E. A., Gollin, S. M., Sukumar, S., Sidransky, D. & Trink, B. (2006). Overexpression of glycosylphosphatidylinositol (GPI) transamidase subunits phosphatidylinositol glycan class T and/or GPI anchor attachment 1 induces tumorigenesis and contributes to invasion in human breast cancer. Cancer Res 66, 9829-36.
Wu, G., Xing, M., Mambo, E., Huang, X., Liu, J., Guo, Z., Chatterjee, A., Goldenberg, D., Gollin, S. M., Sukumar, S., Trink, B. & Sidransky, D. (2005). Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 7, R609-16.
Wu, J., M. J. Fackler, M. K. Halushka, D. Molavi, M. E. Taylor, W. W. Tao, C. Griffin, J. Fetting, N. E. Davidson, A. M. De Marzo, J. Hicks, D. Chitale, M. Ladanyi, S. Sukumar, and P. Argani. 2008. Heterogeneity of breast cancer metastasis: comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases. . Clin Cancer Res 14:1938-1946.
Wu, J.M., Fackler, M.J., Halushka, M.K., Molavi, D.W., Taylor, M.E., Teo, W.W., Griffin, C., Fetting, J., Davidson, N.E., De Marzo, A.M., Hicks, J.L., Chitale, D., Ladanyi, M., Sukumar, S., and Argani, P. (2008). Heterogeneity of breast cancer metastases: comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases. Clin Cancer Res 14, 1938-1946.
Wu, X., and S. Sukumar. 2007. ETS genes in breast cancer: a step in the right direction. Cancer Biol Ther 6:83-4.
Wu, X., Chen, H., Parker, B., Rubin, E., Zhu, T., Lee, J. S., Argani, P. & Sukumar, S. (2006). HOXB7, a Homeodomain Protein, Is Overexpressed in Breast Cancer and Confers Epithelial-Mesenchymal Transition. Cancer Res 66, 9527-34.
Chen, H., Chung, S., & Sukumar, S. 2004. HOXA5-induced apoptosis in breast cancer cells is mediated by caspases 2 and 8. Mol. Cell. Biol. 24:924-935.
Fackler, M. J., McVeigh, M., Mehrotra, J., Blum, M. A., Lange, J., Lapides, A., et al. 2004. Quantitative multiplex methylation-specific PCR assay for the detection of promoter hypermethylation in multiple genes in breast cancer. Cancer Res. 64:4442-4452.
Kominsky, S. L., Vali, M., Korz, M., Gabig, T. G., Weitzman, S. A., Argani, P., et al. 2004. Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am. J. Pathol. 164:1627-1633.
Mehrotra, J., Ganpat, M. M., Kanaan, Y., Fackler, M. J., McVeigh, M., Lahti-Domenici, J., et al. 2004. Estrogen receptor/progesterone receptor-negative breast cancers of young African-American women have a higher frequency of methylation of multiple genes than those of Caucasian women. Clin. Cancer Res. 10:2052-2057.
Mehrotra, J., Vali, M., McVeigh, M., Kominsky, S. L., Fackler, M. J., Lahti-Domenici, J., et al. 2004. Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung. Clin. Cancer Res. 10:3104-3109.
Parker, B. S., Argani, P., Cook, B. P., Han, L., Chatrand, S. D., Zhang, M., et al. 2004. Alterations in vascular gene expression in invasive breast carcinoma. Cancer Res. 64:7857-7866.
Zhu, T., & Sukumar, S. 2004. Coupling the transcriptional regulatory action of brn-3b to the cell cycle clock. Cancer Biol. Ther. 3:324-325.
