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: 8433522
• 负责人: Rajeev S Samant
• 金额: $ 24.97万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/8433522
• 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相互作用者（NMI）在癌症中的作用 生物学[1]。当我们看到它的表达是 在侵略性的乳腺癌细胞系中减少。有趣的是，NMI表达可能是 使用干扰素 - 在这些细胞中诱导[1]。我们发现诱导的mRNA具有野生类型 序列，表明诱导的NMI蛋白具有正常的生物学活性。测试 它的功能作用，我们在人类乳腺癌细胞系MDA-MB-中的组成性表达NMI 231。表达式的功能研究表明，NMI降低了肿瘤细胞侵袭的能力 并在独立条件下生长。裸鼠的异种移植研究表明NMI 表达在体内肿瘤的生长降低[1]。 对这些表达式的进一步分析表明，dickkopf -1（DKK1）是Wnt/®的可溶性抑制剂 - Catenin信号通路，在NMI表达克隆并发同时进行了显着更新 Wnt途径的临界转录共同因素的水平降低了 - 帕宁蛋白。 dkk1曾经 据报道，在涉及乳腺癌的几项研究中抑制原发性肿瘤的生长率[2，3]，IS IFN-€引起的抗肿瘤效应的涉及的因素[4]。 Wnt/¿-Catenin信号很重要 在发育和细胞增殖中。虽然先前证明是颜色的关键玩家 癌症的进展，Wnt/�-蛋白质信号在乳腺癌中的作用尚未明确定义[5]。 这项拟议工作的总体目的是了解Wnt/� -Catenin信号的调节 由NMI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对Wnt/¿-Catenin信号传导途径的抑制至关重要 NMI减少肿瘤生长。 目的1：测试敲低NMI表达的假设将激活Wnt/®-Catenin 信号。 目的2：确定NMI调节DKK1和 - 帕宁的调节机理。 目标3：评估DKK1在介导NMI肿瘤生长延迟中的作用。 目标4：确定NMI表达丧失与激活的Wnt/® -Catenin之间的相关性 患者衍生的乳腺癌标本中的信号传导。