Malathy Puthan Shekhar
Malathy Puthan Shekhar
Office AddressE204 Prentis Cancer Ctr
Karmanos Cancer Institute
4100 John R
Detroit, MI 48201
Ph.D., Indian Institute of Science, 1985
Areas of InterestBreast Cancer Program
Our research interest is focused on understanding the mechanisms that influence responsiveness/resistance of breast cancer cells to hormones or chemotherapy. It is a well known fact that a third of ERa+ breast tumors fail to respond to antiestrogens despite retention of ERa expression, and majority of ERa+ tumors subsequently develop resistance to antiestrogens. Our hypothesis is that the stromal microenvironment plays a dominant role in influencing or modulating hormonal responsiveness of the breast epithelium. We have developed a novel three-dimensional model system that permits reciprocal interactions between breast stromal cells and epithelial cells, and produces phenotypic changes in the epithelium that are reminiscent of those observed in vivo. This 3-D coculture system allows us to delineate the effects of normal versus tumor-derived stroma on normal versus premalignant breast epithelial cells. We are currently using this system to evaluate functional roles/effects of tumor-derived stroma on breast epithelial growth and response to estrogen/antiestrogens. Towards understanding mechanisms regulating response/resistance to chemotherapeutic drugs, we have identified and characterized the gene Rad6B. Like Rad51, which is a fundamental component of recombination dependent DNA repair, Rad6 is a fundamental component of the postreplication DNA repair or error-prone repair pathway. It is a ubiquitin conjugating enzyme and its function is dependent upon its ubiquitin conjugating activity. Mutation of the ubiquitin conjugating catalytic site renders the cells hypersensitive to a variety of DNA damaging agents; conversely, overexpression of the wild type Rad6 induces resistance to a variety of DNA damaging agents. Our studies have shown that tight regulation of Rad6 expression is essential for maintenance of genomic integrity of breast cells. Rad6 is physically complexed with p53, and treatment with chemotherapeutic drugs results in recruitment of p14ARF into Rad6-p53 complexes and monoubiquitination of p53. Interaction and stabilization of p53 by Rad6 during DNA damage response is required for maintenance of the fidelity of repair process.
Shekhar, P.V.M., Werdell, J, Santner, S., Pauley, R.J., and Tait, L Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression. Cancer Res., 61, 1320-1326, 2001.
Shekhar, P.V.M., Lyakhovich, A., Heng, H., Visscher, D.W.. and Kondrat, N. RAD6 overexpression induces centrosome amplification, abnormal mitosis, aneuploidy and transformation. Cancer Res., 62:2115-2124,2002.
Lyakhovich, A. and Shekhar, P.V.M. Supramolecular complex formation between Rad6 and proteins of p53 pathway during DNA damage-induced response. Mol. and Cell. Biol, 23: 2463-2475, 2003.
Lyakhovich, A. and Shekhar, P.V.M. RAD6B overexpression confers chemoresistance: RAD6 distribution during cell cycle, and its redistribution to chromatin during DNA damage-induced response. Oncogene, 23:3098-3107, 2004.
Shekhar, P.V.M., Nangia-Makker, P, Tait, L, Miller, F, and Raz, A. Alterations in galectin-3 expression and distribution correlate with breast cancer progression: Functional analysis of galectin-3 in breast epithelial-endothelial interactions. Amer. J Pathol., 165: 1931-1941, 2004.
Shekhar, P.V.M., Tait, L., and Gerard, B. Essential role of TCF/b-catenin in regulation of Rad6B: A potential mechanism for Rad6B overexpression in breast cancer cells. Mol. Cancer Res., 4: 729-745, 2006.
Zhao, J., Zhu, K., Lubman, D., Miller, F., Shekhar, P.V.M., Gerard, B., and Barder, T.J. Proteomic analysis of estrogen response of premalignant human breast cells using a 2-D liquid separation/mass mapping technique. Proteomics, 6: 3847-3861, 2006.
Shekhar P.V.M., Santner S, Carolin-Amirikia K., and Tait, L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Amer. J Pathol, 170:1546-1560, 2007.
Nangia-Makker, P., Tait, L, Shekhar, P.V.M., Palomino, E., Hogan, V., Funasaka, T., and Raz, A. Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum gratissimum. Int J Cancer, April 16, E Pub, 2007.
Shekhar, P.V.M. and Larry Tait. Breast cancer stem cell paradigm. In: Stem Cells and Cancer" (Ed. Devon W. Parsons), Nova Science Publishers, Hauppauge, NY, pp. 47-64, 2007.