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

我们目前的研究表明，BCL9-2作为典型wnt信号的辅助因子，可能在肠道和乳腺肿瘤发生中发挥重要作用。我们培育了Tg（K19-Bcl9-2）小鼠，发现了小肠和胰腺去分化肿瘤的形成。化合物Tg(K19-Bcl9-2) x APCMin/+小鼠显示腺瘤形成增加，局部侵袭，生存率降低。Tg（K19- Bcl9-2）雌性小鼠发生乳腺癌前病变和高分化的ER*乳腺癌，包括管腔和肌上皮细胞系。BCL9-2调节结肠癌细胞中Wnt/ß-catenin靶基因的一个子集，以及其他可能独立于ß-catenin的基因。在第二个资助期，我们将阐明BCL9-2调控的靶基因在体外和体内的转录控制和作用，例如CDX1/CDX2， EphrinB和其他在我们的微阵列中发现的新靶基因。此外，我们将描述SCL9-2对EMT的诱导和E-cadherin表达的调节。其次，我们将重点研究BCL9-2在人和小鼠模型中诱导的乳腺肿瘤发生。我们将分析乳腺癌细胞BCL9-2和激素受体的表达，并对细胞进行RNA干扰。我们将确定乳腺细胞中内质网的表达和功能是否受BCL9-2的调节。此外，我们将在生物检测中分析小鼠乳腺组织的原代培养及其对类固醇和Wnt治疗的反应性。原代细胞将被分类为干细胞标记物，以鉴定转化的祖细胞和假定的癌症干细胞。分类后的干细胞将在体外和体内进一步分析。这些研究将阐明BCL9-2在乳腺癌发生发展中的作用。

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.