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相互作用因子（Nmi）在癌症中的作用 生物学[1]。当我们看到它的表达是 在侵袭性乳腺癌细胞系中减少。有趣的是，Nmi的表达可能是 在这些细胞中使用干扰素-<$（IFN-<$）诱导[1]。我们发现，诱导的mRNA具有野生型 序列分析表明，诱导表达的Nmi蛋白具有正常的生物学活性。测试 其功能作用，我们组成型表达Nmi在人乳腺癌细胞系，MDA-MB- 231.表达子的功能研究表明，Nmi降低了肿瘤细胞侵袭的能力 并在不依赖锚定的条件下生长。裸鼠异种移植研究表明，Nmi 在体内，表达者的肿瘤生长减少[1]。 对这些表达子的进一步分析表明，Dickkopf-1（Dkk 1），一种可溶性Wnt/Wnt抑制剂， 连环蛋白信号通路，在Nmi表达克隆中显著上调， 降低Wnt途径的关键转录辅因子--连环蛋白的水平。DKK 1已经 据报道，在涉及乳腺癌的几项研究中抑制原发性肿瘤生长率[2，3]， 一种与IFN-γ引起的抗肿瘤作用有关的因子[4]。Wnt/β-catenin信号传导很重要 在发育和细胞增殖中的作用。虽然以前被证明是结肠癌的关键球员， 尽管Wnt/β-catenin信号在乳腺癌进展中的作用尚未明确[5]。 这项工作的总体目标是了解Wnt/连环蛋白信号转导的调控 通过Nmi，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Dkk 1来抑制Wnt/<$-连环蛋白信号传导通路对于以下作用至关重要： 减少肿瘤生长。 目的1：验证Nmi表达的敲低将激活Wnt/â-连环蛋白的假设 发信号。 目的2：探讨Nmi对Dkk 1和<$-catenin的调控机制。 目的3：探讨Dkk 1在Nmi抑制肿瘤生长中的作用。 目的4：确定Nmi表达缺失与活化Wnt/<$-连环蛋白之间的相关性 患者来源的乳腺癌样本中的信号传导。