Research in our laboratory focuses on understanding the role of N-Myc interactor (Nmi) in cancer biology . Our interest in this molecule was triggered when we saw that its expression was diminished in aggressive breast cancer cell lines. Interestingly though, Nmi expression could be induced in these cells using interferon-? (IFN-?) . We found that the induced mRNA had a wild type sequence, implying that the induced Nmi protein was capable of its normal biological activities. To test its functional role, we constitutively expressed Nmi in the human breast cancer cell line, MDA-MB- 231. Functional studies of the expressors showed that Nmi reduced the ability of tumor cells to invade and grow under anchorage independent conditions. Xenograft studies in nude mice showed that Nmi expressors had reduced tumor growth in vivo . Further analysis of these expressors revealed that Dickkopf-1 (Dkk1), a soluble inhibitor of the Wnt/?- catenin signaling pathway, was significantly upregulated in the Nmi expressing clones concurrent with reduced levels of the critical transcription co-factor of Wnt pathway, ?-catenin. Dkk1 has been reported to suppress primary tumor growth rates in several studies involving breast cancer [2, 3] and is a factor implicated in the anti-tumor effects elicited by IFN-? . Wnt/?-catenin signaling is important in development as well as cell proliferation. While previously shown to be a critical player in colon cancer progression, the role of Wnt/?-catenin signaling in breast cancer is not clearly defined . The overall objective of this proposed work is to understand the regulation of Wnt/?-catenin signaling by Nmi and to determine the role of this pathway in suppression of breast tumor growth. HYPOTHESIS Inhibition of the Wnt/?-catenin signaling pathway by upregulation of Dkk1 is critical to the role of Nmi in reducing tumor growth.
Aim 1 : To test the hypothesis that knockdown of Nmi expression will activate the Wnt/?-catenin signaling.
Aim 2 : To determine the mechanism of regulation of Dkk1 and ?-catenin by Nmi.
Aim 3 : To evaluate the role of Dkk1 in mediating the retardation of tumor growth by Nmi.
Aim 4 : To determine correlation between loss of Nmi expression and activated Wnt/?-catenin signaling in patient derived breast cancer specimens.
Our preliminary data demonstrates a functional role of Nmi in retarding breast tumor growth.This proposal takes the research to a next essential step in establishing the translational potentialof Nmi and the downstream events that it regulates. The focus of this research is the Wnt/ -catenin pathway. Nmi up-regulates Dkk1; a secreted inhibitor of Wnt pathway; leading us topropose that Nmi down regulates Wnt/ -catenin signaling; resulting in reduced malignant activityof breast cancer.
|Devine, D J; Rostas, J W; Metge, B J et al. (2014) Loss of N-Myc interactor promotes epithelial-mesenchymal transition by activation of TGF-*/SMAD signaling. Oncogene 33:2620-8|
|Rostas 3rd, Jack W; Pruitt, Hawley C; Metge, Brandon J et al. (2014) microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer. Mol Cancer 13:200|
|Shevde, Lalita A; Samant, Rajeev S (2014) Nonclassical hedgehog-GLI signaling and its clinical implications. Int J Cancer 135:1-6|
|Shevde, Lalita A; Samant, Rajeev S (2014) Role of osteopontin in the pathophysiology of cancer. Matrix Biol 37:131-41|
|Das, Shamik; Samant, Rajeev S; Shevde, Lalita A (2013) Nonclassical activation of Hedgehog signaling enhances multidrug resistance and makes cancer cells refractory to Smoothened-targeting Hedgehog inhibition. J Biol Chem 288:11824-33|
|Menezes, Mitchell E; Devine, Daniel J; Shevde, Lalita A et al. (2012) Dickkopf1: a tumor suppressor or metastasis promoter? Int J Cancer 130:1477-83|
|Andrews, Joel F; Sykora, Landon J; Letostak, Tiasha Barik et al. (2012) Cellular stress stimulates nuclear localization signal (NLS) independent nuclear transport of MRJ. Exp Cell Res 318:1086-93|
|Menezes, Mitchell E; Mitra, Aparna; Shevde, Lalita A et al. (2012) DNAJB6 governs a novel regulatory loop determining Wnt/?-catenin signalling activity. Biochem J 444:573-80|
|Harris, L G; Pannell, L K; Singh, S et al. (2012) Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61. Oncogene 31:3370-80|
|Das, Shamik; Tucker, J Allan; Khullar, Shikha et al. (2012) Hedgehog signaling in tumor cells facilitates osteoblast-enhanced osteolytic metastases. PLoS One 7:e34374|
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