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Shyamala Maheswaran, PhD

Associate Professor, Department of Surgery, Harvard Medical School

Associate in Molecular Biology, Surgery, Massachusetts General Hospital

Contact Info

Shyamala Maheswaran
Massachusetts General Hospital
55 Fruit Street
Boston, MA, 02114
Mailstop: Jackson 904
Phone: 617-724-6552
Fax: 617-726-8623
maheswaran@helix.mgh.harvard.edu

Assistant

Not Available.

DF/HCC Program Affiliation

Gynecologic Cancers

Research Abstract

My research is focused on characterizing the molecular mechanisms governing development and tumorigenesis of the mammary gland using Mullerian Inhibiting Substance (MIS)-mediated inhibition of breast cancer cell growth as a model system, with emphasis on determining molecular targets for mechanism-based treatment strategies and identifying potential molecular markers to predict risk and for early disease detection. MIS, a member of the TGF superfamily, causes the regression of the Mullerian duct in the male embryos. It signals by binding to transmembrane serine threonine kinase receptors, which propagate intracellular signaling. Until recently, the MIS receptors were thought to have a restricted pattern of expression. However, we recently demonstrated the presence of MIS receptors in the breast (Segev et al., 2000) suggesting that this nongonadal tissue is a likely target for MIS action. MIS inhibited the growth of breast cancer cells in vitro through a mechanism that requires activation of the NFkB pathway (Hoshiya et al., 2003b; Segev et al., 2000; Segev et al., 2002; Segev et al., 2001). Using a mouse model with spontaneously arising mammary tumors and human breast cancer xenografts established in immune compromised mice, we have demonstrated that MIS delays tumor progression and growth by preventing proliferation and programmed cell death (Gupta et al., 2005). This observation is now being validating in various nonimmunosuppressed mouse mammary tumor models using a larger cohort of animals. These data raise the possibility that the growth inhibitory effects of MIS could be beneficial in the treatment/prevention of hormone refractory mammary tumors (Gupta et al., 2005). It is noteworthy that high levels of MIS have not shown any harmful effects in humans, and the serum levels of MIS needed to inhibit mammary tumor growth in vivo are well below those sustained in normal healthy postnatal to prepubertal boys.
In order to determine whether MIS-mediated signaling could provide a potential site for mechanism-based intervention of tumor growth, using cDNA microarrays, we identified several MIS-inducible genes including the interferon Regulatory Factor-1 (IRF-1) (Hoshiya et al., 2003a), B-cell Translocation Gene-2 (BTG2) (Kawakubo et al., 2004), and Gro-, a chemokine, and further characterized them. MIS by virtue of inducing IRF-1 intersected with signaling by interferon-g (IFN-g), a cytokine with anti-tumor activity, and enhanced IFN-g-induced gene expression and apoptosis of breast cancer cells suggesting a functional interaction between these two signaling molecules (Hoshiya et al., 2003a). Although the anti-tumor effect of IFN-g in vivo has been well documented, toxicity associated with exposure to IFN-g has diminished its utility in treatment. The ability of MIS to augment IFN-g induced apoptosis of breast cancer cells, suggests that MIS may prove to be beneficial in harnessing the anti-tumor effects of this cytokine, especially since high levels of MIS have not shown any harmful effects in humans. This unique hypothesis derived from experimental observations is being now tested in vivo, using the mouse model systems in which MIS suppressed tumor progression and growth.
The BTG2 gene localizes to chromosomal locus 1q32, and loss of heterozygosity at 1q23-32 appears to be one of the lesions associated with development of breast cancer. However, little is known about the role of BTG2 in mammary gland development and tumorigenesis. In the rat mammary glands, BTG2 was expressed in epithelial cells and levels decreased during pregnancy and lactation but recovered during involution. Estrogen and progestin suppressed BTG2 expression suggesting that these steroids, which stimulate proliferation and lobuloalveolar development of mammary epithelial cells, may down-regulate BTG2 in the mammary gland during pregnancy. Consistent with the report that BTG2 inhibits cyclinD1 expression, suppression of BTG2 mRNA in the mammary gland during gestation, and by estrogen and progestin correlated with stimulation of cyclinD1. Ectopic

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