The role of the novel BCL9/BCL9-2 oncoproteins in tumorigenesis

新型 BCL9/BCL9-2 癌蛋白在肿瘤发生中的作用

• 批准号: 45707582
• 负责人: Professor Dr. Felix H. Brembeck
• 金额: --
• 依托单位: Klinik für Hämatologie und Medizinische Onkologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/45707582?language=en
• 关键词: role; novel; BCL9; oncoproteins; tumorigenesis

Our current investigations indicated that BCL9-2, a cofactor of canonical Wnt-signaling, might play an essential role in intestinal and mammary tumorigenesis. We have developed Tg(K19-Bcl9-2) mice and found the formation of dedifferentiated intestinal and pancreatic tumors. Compound Tg(K19-Bcl9-2) x APCMin/+ mice showed increased adenoma formation, local invasion and decreased survival. Tg(K19- Bcl9-2) female mice developed premalignant alterations of the breast and well differentiated, ER* mammary cancers consisting of luminal and myoepithelial lineages. BCL9-2 regulated a subset of Wnt/ß-catenin target genes in colon cancer cells and in addition other genes, possibly independently of ß-catenin. In the second funding period, we will elucidate the transcriptional control and the role of BCL9-2 regulated target genes in vitro and in vivo, e.g. of CDX1/CDX2, EphrinB, and other novel target genes identified in our microarrays. Moreover, we will characterize the induction of EMT by SCL9-2 and the regulation of E-cadherin expression. Secondly, we will focus on BCL9-2 induced mammary tumorigenesis in human and in mouse models. Mammary cancer cells will be analyzed for BCL9-2 and hormone receptors expression, and we will perform RNA interference in the cells. We will characterize if ER expression and function is regulated by BCL9-2 In mammary cells. Furthermore, we will analyze primary cultures of mouse breast tissues in biological assays and their responsiveness to steroids and Wnt treatment. Primary cells will be sorted for stem cell markers to identify transformed progenitors and putative cancer stem cells. Sorted stem cells will be further analyzed in vitro and in vivo. These studies will elucidate the role of BCL9-2 in breast cancer development and progression.

我们目前的研究表明，BCL 9 -2，一个典型的Wnt信号的辅因子，可能在肠道和乳腺肿瘤的发生中发挥重要作用。我们已经开发了Tg（K19-Bcl 9 -2）小鼠，并发现了去分化的肠和胰腺肿瘤的形成。化合物Tg（K19-Bcl 9 -2）x APCMin/+小鼠显示增加的腺瘤形成、局部侵袭和降低的存活。Tg（K19-Bcl 9 -2）雌性小鼠发生乳腺癌前病变和分化良好的ER* 乳腺癌，包括管腔和肌上皮谱系。BCL 9 -2调节结肠癌细胞中Wnt/β-连环蛋白靶基因的一个亚组以及其他基因，可能独立于β-连环蛋白。在第二个资助期，我们将阐明转录控制和BCL 9 -2调节的靶基因在体外和体内的作用，例如CDX 1/CDX 2，EphrinB和我们的微阵列中鉴定的其他新靶基因。此外，我们将描述由SCL 9 -2诱导的EMT和E-cadherin表达的调节。其次，我们将集中在BCL 9 -2诱导的乳腺肿瘤在人类和小鼠模型。将分析乳腺癌细胞的BCL 9 -2和激素受体表达，我们将在细胞中进行RNA干扰。我们将研究乳腺细胞中ER的表达和功能是否受BCL 9 -2的调控。此外，我们还将分析小鼠乳腺组织的原代培养物的生物测定及其对类固醇和Wnt治疗的反应性。将对原代细胞进行干细胞标志物分选，以鉴定转化的祖细胞和推定的癌症干细胞。分选的干细胞将在体外和体内进一步分析。这些研究将阐明BCL 9 -2在乳腺癌发生和发展中的作用。