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。这是美国女性癌症死亡的第二大原因。化学疗法在控制乳腺癌中起着重要作用。在早期乳腺癌中，化疗将复发的年几率降低24％，死亡率减少了15％。紫杉烷（紫杉醇和多西他赛）和蒽环类药物（阿霉素，表蛋白蛋白皮蛋白）是用于治疗乳腺癌的最活跃的药物之一。但是，初始响应后的非反应者和失败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的表达丧失，MCJ是副伴侣DNAJ家族的相对较新的成员，已显示与卵巢癌患者的化学疗法反应差和生存不良相关。我们最近首次表明，MCJ在对化学治疗药物敏感的人类乳腺癌细胞中表达，但其表达在多药耐药性乳腺细胞中丧失。此外，由于特异性ABC转运蛋白基因通过C-JUN的上调，抑制药物敏感的癌细胞系中MCJ表达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表达的丧失会在体内促进多药耐药性。为了实现我们的目标，我们已经确定并表征了鼠标中人类MCJ的直系同源物。为了证明在小鼠乳腺癌细胞中不存在MCJ会增强对体内化学疗法的抵抗力（特定目的1），我们建议使用：1）MCJ缺乏小鼠和2）在乳腺组织中特异性MCJ的转基因小鼠。为了证明人类乳腺癌细胞中MCJ的丧失会促进体内多药耐药性（特定目标2），我们将使用在免疫缺陷小鼠中丧失MCJ表达的人类乳腺癌细胞的异种移植。因此，我们将研究MCJ表达丧失的潜在相关性与增强的化学疗法耐药性，而且MCJ表达的丧失是否是多药抗性的原因。虽然对人乳腺组织中MCJ表达的分析可以提供相关信息，但我们的研究将证明MCJ表达和多药耐药性丧失的原因。考虑到多药耐药性是乳腺癌治疗中的第一问题，这些研究非常相关。