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: 8038299
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038299
• 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; public health relevance; small molecule; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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 potential of 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 to propose that Nmi down regulates Wnt/?-catenin signaling, resulting in reduced malignant activity of breast cancer.

描述（由申请人提供）：我们实验室的研究重点是了解N-Myc相互作用物（Nmi）在癌症生物学中的作用。当我们看到它在侵袭性乳腺癌细胞系中的表达减少时，我们对这种分子的兴趣就被激发了。有趣的是，Nmi的表达可以在这些细胞中使用干扰素-？(IFN - ?)[1]。我们发现，诱导的mRNA具有野生型序列，这意味着诱导的Nmi蛋白具有正常的生物活性。为了测试其功能作用，我们在人乳腺癌细胞系MDA-MB- 231中组成表达Nmi。表达物的功能研究表明，Nmi降低了肿瘤细胞在非锚定条件下的侵袭和生长能力。裸鼠异种移植研究表明，Nmi表达物在体内抑制肿瘤生长。