Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

描述（由申请人提供）：Mucin 1 （MUC1）在约90%的人类乳腺癌中异常过表达，因此被认为是开发新的抗癌药物的一个极具吸引力的靶点。然而，由于缺乏对MUC1如何促进恶性进展的理解，在鉴定阻断MUC1的药物方面的进展受到限制。在这方面，MUC1由两个亚基组成，早期的研究主要集中在胞外粘蛋白亚基（MUC1- n）上。该基金支持的工作现已证明，跨膜MUC1-C亚基作为癌蛋白起作用，并且是开发新型治疗剂的可药物靶点。Muc1 - c代表了一个潜在的选择性靶标，因为Muc1敲除小鼠是可行的，没有明显的表型。此外，MUC1-C亚基通常位于乳腺上皮细胞的顶端边缘，处于无活性状态。随着转化和极性的丧失，MUC1-C与乳腺癌细胞膜上的受体酪氨酸激酶结合，定位于细胞质、细胞核和线粒体。MUC1-C抑制剂在治疗小鼠乳腺肿瘤异种移植瘤中非常有效，且无正常组织毒性，这进一步支持了MUC1-C作为靶标的潜在选择性。本研究的总体目标是通过阻断MUC1-C致癌功能的新方法靶向MUC1-C，提高科学知识、治疗能力和临床实践。我们的假设是MUC1-C癌蛋白是一个可药物靶点，可以在细胞膜和乳腺癌细胞内被抑制。这项工作将通过提供(i) MUC1-C功能抑制如何阻断乳腺癌细胞生长和存活的新见解，以及（ii）新的治疗药物将在临床前评估乳腺癌临床治疗的潜在发展来解决这一假设。具体目的是：(1)评估针对乳腺癌细胞表面MUC1-C亚基胞外结构域的潜在治疗方法；(2)评价可阻断MUC1-C在细胞质中功能的口服生物可利用型MUC1-C肽抑制剂的开发；(3)确定细胞核和线粒体中MUC1-C功能的肽和小分子抑制剂的活性；(4)确定MUC1-C抑制剂与靶向抗癌药物联合治疗乳腺癌的有效方法。

DESCRIPTION (provided by applicant): Mucin 1 (MUC1) is aberrantly overexpressed in ~90% of human breast cancers and, as such, has been regarded as a highly attractive target for the development of new anti-cancer agents. However, progress in the identification of drugs that block MUC1 had been previously limited by a lack of understanding as to how MUC1 contributes to malignant progression. In this regard, MUC1 consists of two subunits, and early research focused on the shed extracellular mucin subunit (MUC1-N). Work supported by this grant has now demonstrated that the transmembrane MUC1-C subunit functions as an oncoprotein and is a druggable target for the development of novel therapeutic agents. MUC1-C represents a potentially selective target in that the Muc1 knock-out mouse is viable and has no evident phenotype. In addition, the MUC1-C subunit is normally positioned in an inactive state at the apical borders of mammary epithelial cells. With transformation and loss of polarity, MUC1-C associates with receptor tyrosine kinases at the breast cancer cell membrane and localizes to the cytoplasm, nucleus and mitochondria. The potential selectivity of MUC1-C as a target is further supported by the demonstration that MUC1-C inhibitors are highly effective in the treatment of human breast tumor xenografts in mice without normal tissue toxicity. The overall objective of the proposed work is to improve scientific knowledge, therapeutic capability and clinical practice by targeting MUC1-C with novel approaches that block its oncogenic function. Our hypothesis is that the MUC1-C oncoprotein is a druggable target that can be inhibited at the cell membrane and within the breast cancer cell. The proposed work will address this hypothesis by providing (i) new insights into how inhibition of MUC1-C function blocks growth and survival of breast cancer cells, and (ii) new therapeutic agents that will be evaluated preclinically for potential development in the clinic for the treatment of breast cancer. The Specific Aims are: (1) To assess potential therapeutic approaches that target the MUC1-C subunit extracellular domain at the breast cancer cell surface; (2) To evaluate the development of orally bioavailable MUC1-C peptide inhibitors that block its function in the cytoplasm; (3) To define the activity of peptide and small molecule inhibitors of MUC1-C function in the nucleus and mitochondria; and (4) To identify effective combinations of MUC1-C inhibitors with targeted anti-cancer agents for breast cancer treatment. PUBLIC HEALTH RELEVANCE: Breast cancer is one of the leading causes of death for women. The MUC1 oncoprotein is expressed at high levels in approximately 90% of human breast tumors and contributes to carcinogenesis. Our proposed research focuses on the development of new therapeutic agents that target MUC1 for the treatment of patients with breast cancer.