Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

人类乳腺癌中 DF3/MUC1 的致癌信号传导

• 批准号: 6531492
• 负责人: DONALD W. KUFE
• 金额: $ 38.08万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6531492
• 关键词: biological signal transduction; breast neoplasms; cadherins; cell membrane; crosslink; epidermal growth factor; fluorescence microscopy; growth factor receptors; immunofluorescence technique; ligands; mucins; protein localization; protein protein interaction; protein sequence; protooncogene; receptor binding

The DF3/MUC1 transmembrane protein is aberrantly expressed at high levels on the surface of human breast cancer cells. The functional significance of MUC1 overexpression in breast cancer is unknown. Certain insights have been derived from the finding the cytoplasmic domain of MUC1 associates with members of the catenin family of signaling proteins, beta- catenin, plakoglobin and p120ctn. Beta-catenin interacts with E- cadherin at the cell membrane, with the adenomatous polyposis coli (APC) Protein in the cytosol and with Tcf/LEF-1 as a transcriptional coactivator in the nucleus. Dysregulation of beta-catenin signaling has been associated with the development of diverse human tumors. MUC1 suppresses binding of beta-catenin to E-cadherin and thereby disrupts the adherens junction, an event associated with tumor progression. MUC1 associates with the epidermal growth factor receptor (EGFR), ErbB2 (HER2/neu) and the related ErbB3 and ErbB4 receptor tyrosine kinases. Phosphorylation of the MUC1 cytoplasmic domain by activation of EGFR or the c-Src tyrosine kinase increases the interaction between MUC1 and beta-catenin. By contrast, phosphorylation of MUC1 by glycogen synthase kinase 3beta (GSK3beta), an effector of the Wnt signaling pathway, downregulates the interaction between MUC1 and beta-catenin. Our hypothesis is that, as a consequence of overexpression in breast cancer cells, MUM contributes to i) dysregulation of growth factor signaling through EGFR and the related ErbB2-4 receptors and ii) dysfunction of catenin family members at the cell membrane and in the nucleus. The proposed studies will address this hypothesis and whether MUC1 also functions as a cell surface receptor in breast tumor development. The Specific Aims are: 1) To define the functional significance of the interaction between MUC1 and the EGF receptor, 2) To determine whether MUC1 interacts with ErbB2 and other members of the ErbB receptor family; 3) To define the effects of MUC1 on ErbB receptor-mediated signaling of catenins at the cell membrane and in the nucleus; and 4) To identify ligands that function in directly activating MUC1 as a cell surface receptor.

DF 3/MUC 1跨膜蛋白在人乳腺癌细胞表面以高水平异常表达。 MUC 1过表达在乳腺癌中的功能意义尚不清楚。 从MUC 1的胞质结构域与信号蛋白连环蛋白家族的成员β-连环蛋白、斑珠蛋白和p120 ctn相关的发现中已经得到了某些见解。 β-连环蛋白在细胞膜上与E-钙粘蛋白相互作用，在胞质溶胶中与腺瘤性结肠息肉病（APC）蛋白相互作用，在细胞核中与作为转录共激活因子的Tcf/LEF-1相互作用。 β-连环蛋白信号转导的失调与多种人类肿瘤的发生有关。 MUC 1抑制β-连环蛋白与E-钙粘蛋白的结合，从而破坏粘附连接，这是与肿瘤进展相关的事件。MUC 1与表皮生长因子受体（EGFR）、ErbB 2（HER 2/neu）和相关的ErbB 3和ErbB 4受体酪氨酸激酶相关。 通过EGFR或c-Src酪氨酸激酶的激活使MUC 1胞质结构域磷酸化，增加了MUC 1和β-连环蛋白之间的相互作用。 相比之下，糖原合成酶激酶3 β（GSK 3 β）（Wnt信号通路的效应子）对MUC 1的磷酸化下调MUC 1和β-连环蛋白之间的相互作用。 我们的假设是，作为乳腺癌细胞中过表达的结果，MUM有助于i）通过EGFR和相关ErbB 2 -4受体的生长因子信号传导的失调和ii）细胞膜和细胞核中连环蛋白家族成员的功能障碍。 拟议的研究将解决这一假设，以及MUC 1是否也作为乳腺肿瘤发展中的细胞表面受体发挥作用。具体目标是：1）确定MUC 1和EGF受体之间相互作用的功能意义，2）确定MUC 1是否与ErbB 2和ErbB受体家族的其他成员相互作用; 3）确定MUC 1对ErbB受体介导的细胞膜和细胞核中连环蛋白信号传导的影响;和4）鉴定在直接激活MUC 1作为细胞表面受体中起作用的配体。