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: 7885957
• 负责人: Rajeev S Samant
• 金额: $ 27.68万
• 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/7885957
• 关键词: Agonist; Biological; Biological Products; Breast Cancer Cell; Cancer Biology; Cancer cell line; Cell Proliferation; Cells; Chemicals; 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; anticancer research; 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(申请人提供)：我们实验室的研究重点是了解N-Myc相互作用因子(NMI)在癌症生物学中的作用[1]。当我们看到它在侵袭性乳腺癌细胞系中的表达减弱时，我们对这种分子的兴趣就被触发了。但有趣的是，使用干扰素-？可以诱导这些细胞表达NMI。(干扰素-？)[1]。我们发现，诱导后的mRNA具有野生型序列，表明诱导后的NMI蛋白具有正常的生物学活性。为了测试它的功能作用，我们在人乳腺癌细胞系MDA-MB-231中结构性地表达了Nmi。对表达产物的功能研究表明，NMI降低了肿瘤细胞在锚定非依赖条件下的侵袭和生长能力。裸鼠的异种移植研究表明，NMI表达基因降低了体内肿瘤的生长[1]。 对这些表达产物的进一步分析表明，Wnt/β-catenin信号通路的可溶性抑制物Dickkopf-1(Dkk1)在表达NMI的克隆中显著上调，同时Wnt途径的关键转录辅助因子-β-catenin水平降低。Dkk1在几项涉及乳腺癌的研究中已被报道抑制原发肿瘤的生长速度[2，3]，并且是干扰素-1诱导的抗肿瘤作用中的一个因素[4]。Wnt/？-catenin信号在发育和细胞增殖过程中起着重要作用。虽然以前被证明在结肠癌进展中起关键作用，但Wnt/？-catenin信号在乳腺癌中的作用没有明确的定义[5]。 这项拟议工作的总体目标是了解NMI对Wnt/β-catenin信号的调节，并确定该途径在抑制乳腺肿瘤生长中的作用。 假设 通过上调Dkk1抑制Wnt/β-catenin信号通路是NMI抑制肿瘤生长的关键。 目的1：验证NMI基因表达下调将激活Wnt/β-catenin信号的假设。 目的2：探讨NMI对Dkk1和β-catenin的调节机制。 目的：探讨Dkk1在NMI抑制肿瘤生长中的作用。 目的：探讨乳腺癌组织中NMI基因表达缺失与Wnt/β-catenin信号转导通路激活的相关性。 公共卫生相关性：我们的初步数据表明，NMI在抑制乳腺肿瘤生长方面发挥了作用。这一建议将研究带入了下一个关键步骤，即确定NMI及其调控的下游事件的翻译潜力。本研究的重点是Wnt/？-catenin途径。NMI上调Wnt途径的分泌型抑制因子Dkk1的表达，导致我们提出NMI下调Wnt/β-catenin信号转导，从而降低乳腺癌的恶性活动。