MCJ function in mouse mammary tumor properties

MCJ 在小鼠乳腺肿瘤特性中的功能

• 批准号: 7390544
• 负责人: Mercedes Rincon
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-07 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390544
• 关键词: ATP-Binding Cassette Transporters; Address; Anthracycline Antibiotics; Anthracyclines; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cancer Etiology; Cancer Patient; Cancer cell line; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; CpG Islands; DNA Methylation; Development; Doxorubicin; Doxorubicin/Paclitaxel; Drug resistance; Drug usage; Drug-sensitive; Effectiveness; Epirubicin; Failure; Family; Gene Expression; Genes; Goals; Golgi Apparatus; Human; Immunodeficient Mouse; In Vitro; Individual; Innovative Therapy; JUN gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Methylation; Molecular; Molecular Chaperones; Multi-Drug Resistance; Mus; Numbers; Orthologous Gene; Paclitaxel; Pharmaceutical Preparations; Play; Property; Protein Family; Proteins; Recurrence; Resistance; Role; Small Interfering RNA; Taxane Compound; Time; Tissues; Transgenic Mice; United States; Up-Regulation; Vertebrates; Woman; Xenograft Model; Xenograft procedure; cancer therapy; chemotherapy; docetaxel; heat-shock proteins 40; improved; in vivo; malignant breast neoplasm; member; mouse model; novel; ovarian neoplasm; prevent; response; taxane; transcription factor; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Breast cancer is one of the most common cancers in humans. It is the second leading cause of cancer death among women in United States. Chemotherapy plays an important role in the control of breast cancer. In early breast cancer, chemotherapy decreases the annual odds of recurrence by 24% and odds of death by 15%. Taxanes (paclitaxel and docetaxel) and anthracyclines (doxorubicin, epirubicin) are among the most active drugs used in the treatment of breast cancer. The percentage of non-responders and of failures following an initial response however remains relatively high. Understanding the molecular mechanisms of drug resistance is therefore of major importance. Loss of expression of MCJ, a relatively new identified member of the DnaJ family of co-chaperones, has been shown to correlate with poor chemotherapy response and poor survival in ovarian cancer patients. We have recently shown for the first time that MCJ is expressed in human breast cancer cells that are sensitive to chemotherapeutic drugs, but its expression is lost in multidrug resistant breast cells. Furthermore, inhibition of MCJ expression in drug-sensitive cancer cell lines induces multidrug resistance in vitro by preventing intracellular accumulation of chemotherapeutic drugs due to the upregulation of specific ABC transporter gene expression through c-Jun. Here we propose to demonstrate that loss of MCJ expression in breast tumors promotes multidrug resistance in vivo. To achieve our goals we have already identified and characterized the ortholog of human MCJ in mouse. To demonstrate that the absence of MCJ in mouse breast cancer cells enhances tumor resistance to chemotherapy in vivo (Specific Aim 1) we propose to use: 1) MCJ deficient mice and 2) transgenic mice expressing a siRNA for MCJ specifically in mammary tissue. To demonstrate that the loss of MCJ in human breast cancer cells promotes multidrug resistance in vivo (Specific Aim 2) we will use xenografts of human breast cancer cells that have lost MCJ expression in immunodeficient mice. Thus, we will investigate, not only a potential correlation of loss of MCJ expression with enhanced chemotherapy resistance, but whether the loss of MCJ expression is a cause of multidrug resistance. While the analysis of MCJ expression in human breast tissue can provide correlative information, our studies will demonstrate a cause-effect of loss of MCJ expression and multidrug resistance. These studies are highly relevant considering that multidrug resistance is number one problem in breast cancer therapy.

描述（由申请人提供）：乳腺癌是人类最常见的癌症之一。它是美国女性癌症死亡的第二大原因。化疗在乳腺癌的控制中发挥着重要作用。对于早期乳腺癌，化疗可将年复发几率降低 24%，将死亡几率降低 15%。紫杉烷类药物（紫杉醇和多西紫杉醇）和蒽环类药物（阿霉素、表柔比星）是治疗乳腺癌最有效的药物。然而，初始响应后未响应者和失败者的百分比仍然相对较高。因此，了解耐药性的分子机制至关重要。 MCJ 是 DnaJ 共伴侣家族中相对较新的成员，MCJ 的表达缺失已被证明与卵巢癌患者化疗反应不佳和生存率低相关。我们最近首次证明MCJ在对化疗药物敏感的人乳腺癌细胞中表达，但在多重耐药乳腺细胞中表达缺失。此外，在药物敏感的癌细胞系中抑制 MCJ 表达，可通过 c-Jun 上调特定 ABC 转运蛋白基因表达，防止化疗药物在细胞内积聚，从而在体外诱导多药耐药性。在这里，我们建议证明乳腺肿瘤中 MCJ 表达的丧失会促进体内多药耐药性。为了实现我们的目标，我们已经在小鼠中鉴定并表征了人类 MCJ 的直向同源物。为了证明小鼠乳腺癌细胞中缺乏 MCJ 会增强肿瘤对体内化疗的抵抗力（具体目标 1），我们建议使用：1）MCJ 缺陷小鼠和 2）在乳腺组织中特异性表达 MCJ siRNA 的转基因小鼠。为了证明人乳腺癌细胞中 MCJ 的丢失会促进体内多药耐药性（具体目标 2），我们将使用在免疫缺陷小鼠中丢失 MCJ 表达的人乳腺癌细胞的异种移植物。因此，我们不仅要研究 MCJ 表达缺失与化疗耐药性增强之间的潜在相关性，还要研究 MCJ 表达缺失是否是多药耐药性的原因。虽然对人类乳腺组织中 MCJ 表达的分析可以提供相关信息，但我们的研究将证明 MCJ 表达丧失和多药耐药性之间的因果关系。考虑到多重耐药性是乳腺癌治疗中的首要问题，这些研究具有高度相关性。