Role of Nmi in retarding breast tumor growth.

我们实验室的研究重点是了解N-Myc相互作用蛋白(NMI)在癌症中的作用 生物学[1]。我们对这种分子的兴趣是在我们看到它的表达是 在侵袭性乳腺癌细胞系中减少。不过，有趣的是，NMI表达式可能是 用干扰素[1]在这些细胞中诱导。我们发现，诱导的mrna具有野生型。 测序结果表明，诱导表达的NMI蛋白具有正常的生物学活性。为了测试 我们在人乳腺癌细胞系MDA-MB中结构性地表达了Nmi。 231.对表达产物的功能研究表明，NMI降低了肿瘤细胞的侵袭能力 并在锚地独立的条件下生长。裸鼠异种移植研究表明，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的可溶性抑制物Dickkopf-1(Dkk1)- 在同时表达NMI的克隆中，连环蛋白信号通路显著上调 Wnt途径的关键转录辅助因子-连环蛋白水平降低。Dkk1已经被 据报道，在几项涉及乳腺癌的研究中抑制了原发肿瘤的生长速度[2，3]，并且是 一个与干扰素抗肿瘤作用有关的因素[4]。WNT/？-连环蛋白信号转导很重要 在发育和细胞增殖过程中。虽然之前被证明是冒号的关键参与者 在癌症进展过程中，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Wnt/β-catenin信号的调节 并确定该通路在抑制乳腺肿瘤生长中的作用。 假设 上调Dkk1对Wnt/β-catenin信号通路的抑制作用 NMI具有抑制肿瘤生长的作用。 目的1：验证NMI基因表达下调将激活Wnt/β-catenin的假设 发信号。 目的：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4：确定NMI表达缺失与Wnt/β-连环蛋白活化的相关性 患者来源的乳腺癌标本中的信号。

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.