Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

描述（由申请人提供）：MUC 1异二聚体癌蛋白在超过90%的人乳腺癌中以高水平异常表达。MUC 1 N-末端亚基（MUC 1-N）是破坏细胞-细胞和细胞-细胞外基质相互作用的粘蛋白型糖蛋白。MUC 1 C-末端亚基（MUC 1-C）与Wnt通路效应子结合，连环蛋白，并作为跨膜受体发挥功能。我们的工作还表明MUC 1与EGFR、ErbB 2、c-Src和GSK 32相互作用，表明MUC 1整合了ErbB受体和Wnt信号通路。该基金支持的其他研究表明，MUC 1-C靶向（i）细胞核，在那里它在基因转录的调节中发挥作用，以及（ii）线粒体，在那里它减弱线粒体外膜的透化。这些发现为MUC 1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，是对MUC 1在乳腺癌中的生物学意义的更精确的理解。我们的假设是，MUC 1的生理功能，在正常的乳腺上皮细胞的保护和MUC 1基因被激活的heregulin（HRG）诱导的应激反应。我们的假设也是MUC 1-C亚基将信号从细胞膜转导到细胞核和线粒体，从而对应激产生生长和存活反应。因此，在大多数人乳腺癌中发现的MUC 1的过表达被认为是一种机制，通过这种机制，MUC 1的生理功能被用于肿瘤生长和存活的异常调节。具体目标是：1）明确MUC 1在乳腺肿瘤发生中的作用; 2）阐明MUC 1在非转化和恶性乳腺上皮细胞中表达上调的机制; 3）确定MUC 1和半乳糖凝集素-3相互作用对细胞表面信号传导的功能意义; 4）确定核MUC 1-C对Wnt靶基因的占据和激活的影响; 5）探讨MUC 1-C在抑制细胞质和线粒体外膜凋亡中的作用。 公共卫生相关性：乳腺癌是妇女死亡的主要原因之一。MUC 1蛋白在实验模型中有助于乳腺癌的发展，并且在超过90%的人类乳腺肿瘤中以高水平表达。我们提出的MUC 1研究应该可以更好地了解乳腺癌的病因，并提供潜在的新治疗机会。

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.