Role of Nmi in retarding breast tumor growth.

我们实验室的研究重点是了解 N-Myc 相互作用子 (Nmi) 在癌症中的作用 生物学[1]。当我们看到它的表达是时，我们对这个分子产生了兴趣 侵袭性乳腺癌细胞系减少。有趣的是，Nmi 表达式可以是 使用干扰素-¿ (IFN-¿) 在这些细胞中诱导[1]。我们发现诱导的mRNA有野生型 序列，表明诱导的 Nmi 蛋白能够发挥其正常的生物活性。测试 为了了解其功能作用，我们在人乳腺癌细胞系MDA-MB-中组成型表达Nmi 231. 表达蛋白的功能研究表明，Nmi 降低了肿瘤细胞侵袭的能力 并在不依赖锚地的条件下生长。裸鼠异种移植研究表明，Nmi 表达蛋白降低了体内肿瘤的生长[1]。 对这些表达蛋白的进一步分析表明，Dickkopf-1 (Dkk1) 是 Wnt/¿- 的可溶性抑制剂 连环蛋白信号通路在 Nmi 表达克隆中显着上调 Wnt 通路关键转录辅因子 ¿-连环蛋白的水平降低。 Dkk1 已经 据报道，在几项涉及乳腺癌的研究中，它可以抑制原发肿瘤的生长速度 [2, 3]，并且 与 IFN-¿ 引起的抗肿瘤作用有关的一个因素 [4]。 Wnt/¿-连环蛋白信号传导很重要 发育和细胞增殖。虽然之前被证明是结肠中的关键角色 随着癌症进展，Wnt/¿-连环蛋白信号传导在乳腺癌中的作用尚不清楚[5]。 这项工作的总体目标是了解 Wnt/¿-连环蛋白信号传导的调节 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 Dkk1 抑制 Wnt/¿-连环蛋白信号通路对于发挥 Nmi 减少肿瘤生长。 目标 1：检验 Nmi 表达敲低将激活 Wnt/¿-连环蛋白的假设 发信号。 目标 2：确定 Nmi 对 Dkk1 和 ¿-catenin 的调节机制。 目标 3：评估 Dkk1 在介导 Nmi 延缓肿瘤生长中的作用。 目标 4：确定 Nmi 表达缺失与 Wnt/¿-连环蛋白激活之间的相关性 患者来源的乳腺癌样本中的信号传导。

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.