Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

描述（由申请人提供）：MUC1异二聚体癌蛋白在超过90%的人类乳腺癌中异常高水平表达。MUC1 n端亚基（MUC1- n）是一种粘蛋白型糖蛋白，可破坏细胞间和细胞外基质的相互作用。MUC1 c末端亚基（MUC1- c）与Wnt通路效应物结合。-连环蛋白，并作为跨膜受体发挥作用。我们的工作还表明MUC1与EGFR、ErbB2、c-Src和GSK32相互作用，表明MUC1整合了ErbB受体和Wnt信号通路。该基金支持的其他研究表明，MUC1-C靶向(i)细胞核，在那里它调节基因转录；（ii）靶向线粒体，在那里它减弱线粒体外膜的通透性。这些发现为MUC1在人类乳腺癌发展中的潜在作用提供了新的见解。现在需要的是，至少在一定程度上，更精确地了解MUC1在乳腺癌中的生物学意义。我们的假设是MUC1在生理上保护正常乳腺上皮细胞，并且MUC1基因被heregulin （HRG）诱导的应激反应激活。我们还假设MUC1-C亚基将信号从细胞膜传导到细胞核和线粒体，从而对应激产生生长和生存反应。因此，在大多数人类乳腺癌中发现的MUC1过表达被认为是MUC1生理功能在肿瘤生长和存活的异常调节中被利用的一种机制。具体目的是：1)明确Muc1在乳腺肿瘤发生中的作用；2)阐明MUC1在非转化和恶性乳腺上皮细胞中表达上调的机制；3)确定MUC1与半乳糖凝集素-3相互作用对细胞表面信号传导的功能意义；4)明确细胞核MUC1-C对Wnt靶基因占据和激活的影响；5)探讨MUC1-C在胞浆和线粒体外膜抑制细胞凋亡中的作用。

DESCRIPTION (provided by applicant): The MUC1 heterodimeric oncoprotein is aberrantly expressed at high levels in over 90% of human breast cancers. The MUC1 N-terminal subunit (MUC1-N) is a mucin-type glycoprotein that disrupts cell-cell and cell-extracellular matrix interactions. The MUC1 C-terminal subunit (MUC1-C) binds to the Wnt pathway effector, ?-catenin, and functions as a transmembrane receptor. Our work has also demonstrated that MUC1 interacts with EGFR, ErbB2, c-Src and GSK32, indicating that MUC1 integrates the ErbB receptor and Wnt signaling pathways. Other studies supported by this grant have demonstrated that MUC1-C is targeted (i) to the nucleus where it functions in the regulation of gene transcription, and (ii) to mitochondria where it attenuates permeabilization of the mitochondrial outer membrane. These findings have provided new insights into the potential role of MUC1 in the development of human breast carcinomas. What is needed now, at least in part, is a more precise understanding of the biologic significance of MUC1 in breast cancer. Our hypothesis is that MUC1 functions physiologically in the protection of normal mammary epithelial cells and that the MUC1 gene is activated by the heregulin (HRG)-induced stress response. Our hypothesis is also that the MUC1-C subunit transduces signals from the cell membrane to the nucleus and mitochondria that confer a growth and survival response to stress. The overexpression of MUC1 as found in most human breast cancers is therefore proposed as a mechanism by which physiologic MUC1 functions have been exploited in the aberrant regulation of tumor growth and survival. The Specific Aims are: 1) To define the role of Muc1 in mammary gland tumorigenesis; 2) To elucidate the mechanisms responsible for upregulation of MUC1 expression in nontransformed and malignant mammary epithelial cells; 3) To determine the functional significance of the interaction between MUC1 and galectin-3 on cell surface signaling; 4) To define the effects of nuclear MUC1-C on occupancy and activation of Wnt target genes; and 5) To assess the role of MUC1-C in restraining apoptosis in the cytosol and at the mitochondrial outer membrane. PUBLIC HEALTH RELEVANCE: Breast cancer is one of the leading causes of death among women. The MUC1 protein contributes to the development of breast cancer in experimental models and is expressed at high levels in over 90% of human breast tumors. Our proposed research on MUC1 should provide a better understanding of the causes of breast cancer and potentially new opportunities for treatment.