Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

描述(申请人提供)：MUC1异二聚体癌蛋白在超过90%的人类乳腺癌中高水平异常表达。MUC1N端亚单位(MUC1N)是一种粘蛋白类糖蛋白，可破坏细胞与细胞、细胞与细胞外基质之间的相互作用。MUC1C端亚单位(MUC1C)与Wnt途径效应器β-连环蛋白结合，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。这笔赠款支持的其他研究表明，MUC1-C的靶向是(I)发挥基因转录调控功能的细胞核，以及(Ii)削弱线粒体外膜通透性的线粒体。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，更准确地了解MUC1在乳腺癌中的生物学意义。我们的假设是，MUC1在生理上起到保护正常乳腺上皮细胞的作用，并且MUC1基因被异丙肾上腺素(hereglin，HRG)诱导的应激反应激活。我们的假设也是，MUC1-C亚基将信号从细胞膜传递到细胞核和线粒体，从而对压力做出生长和生存反应。因此，在大多数人类乳腺癌中发现的MUC1的过度表达被认为是一种生理性MUC1功能被利用来异常调节肿瘤生长和生存的机制。这些研究的具体目的是：1)明确MUC1在乳腺肿瘤发生中的作用；2)阐明MUC1在未转化和恶性乳腺上皮细胞中表达上调的机制；3)确定MUC1和Galectin-3相互作用在细胞表面信号转导中的功能意义；4)确定核MUC1-C对Wnt靶基因的占据和激活的影响；以及5)评估MUC1-C在抑制胞浆和线粒体外膜凋亡中的作用。 公共卫生相关性：乳腺癌是导致女性死亡的主要原因之一。在实验模型中，MUC1蛋白有助于乳腺癌的发展，并且在90%以上的人类乳腺肿瘤中高水平表达。我们提出的关于MUC1的研究应该能更好地了解乳腺癌的原因，并提供潜在的新的治疗机会。

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.