Role of Nmi in retarding breast tumor growth.

Nmi 在延缓乳腺肿瘤生长中的作用。

• 批准号: 8206858
• 负责人: Rajeev S Samant
• 金额: $ 26.9万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-04 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206858
• 关键词: Agonist; Biological; Biological Products; Breast Cancer Cell; Cancer Biology; Cancer cell line; Cell Proliferation; Cells; Chemical Agents; Colon Carcinoma; Data; Development; Developmental Biology; Disease; Event; Genetic Transcription; Interferons; Invaded; Laboratories; Laboratory Research; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mediating; Messenger RNA; Nude Mice; Pathway interactions; Patients; Pharmacologic Substance; Primary Neoplasm; Proteins; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Up-Regulation; Work; Xenograft procedure; drug development; in vivo; inhibitor/antagonist; interest; malignant breast neoplasm; mimetics; neoplastic cell; small molecule; tumor; tumor growth; tumor progression

Research in our laboratory focuses on understanding the role of N-Myc interactor (Nmi) in cancer biology [1]. 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-¿) [1]. 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 [1]. 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-¿ [4]. 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 [5]. 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.

我们实验室的研究重点是了解N-Myc相互作用（Nmi）在癌症中的作用