MCJ function in mouse mammary tumor properties

MCJ 在小鼠乳腺肿瘤特性中的功能

• 批准号: 7807612
• 负责人: Mercedes Rincon
• 金额: $ 9.93万
• 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/7807612
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Address; Adopted; Affect; Alternative Therapies; Antibodies; Area; Award; Biological Assay; Biological Markers; Biological Markers; Breast Cancer Cell; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Line; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Childhood Brain Neoplasm; Chimera organism; Chimerism; Clathrin; Clinical; Clinical Research; Conserved Sequence; CpG Islands; Cytoskeleton; Cytosol; Doxorubicin; Drug Combinations; Drug or chemical Tissue Distribution; Drug resistance; Drug-sensitive; Failure; Family; Frequencies; Funding; Future; Gene Duplication; Gene Expression; Genes; Germ Lines; Goals; Golgi Apparatus; Grant; Health; Heart; Hormonal; Human; Immunodeficient Mouse; In Vitro; Integral Membrane Protein; JUN gene; Kidney; Knockout Mice; Lead; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Mammary gland; Mediating; Methylation; Molecular Chaperones; Multi-Drug Resistance; Mus; Nephroblastoma; Normal tissue morphology; Northern Blotting; Orthologous Gene; Ovarian; Paclitaxel; Pain; Patients; Pattern; Pharmaceutical Preparations; Pilot Projects; Play; Property; Protein Family; Proteins; Publishing; Recovery; Recurrence; Relative (related person); Reporting; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Taxane Compound; Testing; Time; Tissues; Transgenic Mice; Translational Research; Transmembrane Domain; Treatment Protocols; Tumor Cell Line; Tumor Tissue; United States; United States National Institutes of Health; Vertebrates; Vesicle; Western Blotting; Woman; Xenograft Model; Xenograft procedure; aspartyl-proline; base; cancer therapy; cell growth; chemotherapy; clinical practice; design; heat-shock proteins 40; in vivo; male; malignant breast neoplasm; melanoma; member; mouse model; neoplastic cell; novel; overexpression; protein folding; public health relevance; research study; response; response marker; taxane; trafficking; transcription factor; translational study; transmission process; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death among women in United States. Despite the more recent use of hormonal or antibody-based therapy, chemotherapy has been and still is one of the most effective and widely used means of treating breast cancer. In early breast cancer, chemotherapy decreases the annual odds of recurrence by 24% and odds of death by 15%. However, the percentage of non-responders and of failures following an initial response remains relatively high suggesting the presence of variable mechanisms for drug resistance. To date, no clear predictive markers for specific chemotherapy response have been adopted for routine clinical practice. The Methylation Controlled J (MCJ) protein is a relatively new member of the DnaJ protein family of co-chaperones. We have recently shown that MCJ is expressed in drugsensitive breast cancer cells, but its expression is lost in multidrug resistant cells. In addition, we have shown that inhibition of MCJ expression in drug-sensitive cells induces resistance to specific drugs (paclitaxel, doxorubicin) in vitro. In our original funded application (CA127099), we proposed to demonstrate that the loss of MCJ expression in breast tumors promotes multidrug resistance in vivo by 1) using xenograft models of human breast cancer cell lines in immunodeficient mice (Aim 1), and 2) generating MCJ knockout mice to disrupt MCJ expression in mouse mammary tumors (Aim 2). Another important question is whether MCJ expression in breast tumor cells could be considered as a predictive marker for chemotherapy response in breast cancer patients. In response to the Notice NOT-OD-09-058 entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application" we are now requesting a Revision for our current grant to carry out a pilot study where we will examine MCJ expression in tumor tissues of breast cancer patients. Since no previous published studies have examined MCJ in breast tumors the purpose of this Revision application is to find what is the relative frequency of tumors expressing or lacking MCJ within classified groups of breast cancer patients, as well as to find the interaction of MCJ expression with different clinical parameters. This basic information is essential for the design and initiation of a large clinical study examining MCJ in patients receiving a specific chemotherapy treatment. This project is highly relevant for human health, specifically in the area of cancer treatment. PUBLIC HEALTH RELEVANCE: Breast cancer is one of the most common cancers in humans and the second leading cause of cancer related death among women in United States. Chemotherapy is still a common mean to treat breast cancer, but the percentage of non-responders and of failures following an initial response remains relatively high. Several chemotherapeutic drugs or combinations of drugs can be provided to the patients, but there are no biological markers that help to predict which patients may or may not respond to a specific chemotherapeutic regimen. Thus, identifying these predictive markers for chemotherapy through the use of standard clinical assays is highly important. Biological markers predictive of a failure for a given chemotherapy regimen will help to save time, effort and unjustified pain of the patients. An alternative therapy can in these cases be provided. Our recent studies have shown that MCJ is a molecule present in drug sensitive breast cancer cell lines but not in multidrug resistant breast cancer cells. We have also shown that blocking the expression of MCJ in human breast cancer cell lines dramatically increases the resistance of these cells to specific chemotherapeutic drugs in vitro. Thus, we hypothesize that MCJ could be use as a predictive marker for response to these drugs. In this application, we propose to perform a pilot study examining MCJ expression in breast tumor samples to characterize the overall distribution of MCJ in different types of breast cancer. The information obtained from these studies will be fundamental for the initiation of large clinical studies to show whether the lack of MCJ in breast tumors is an indicative of poor response to anthracyclins and/or taxanes. Considering the strong need for chemotherapy response biomarkers in cancer, this project is highly relevant for human health.

描述（由申请人提供）：乳腺癌是美国女性癌症死亡的第二大原因。尽管最近使用了基于激素或抗体的治疗，但化学疗法曾经并且仍然是治疗乳腺癌的最有效和广泛使用的方法之一。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％。但是，初始反应后的非反应者和失败的百分比保持较高，表明存在可变机制以抗药性。迄今为止，尚未针对常规临床实践采用明确的预测标记。甲基化控制的J（MCJ）蛋白是辅助蛋白DNAJ蛋白家族的相对新成员。我们最近表明，MCJ在药物敏感的乳腺癌细胞中表达，但其表达在多药耐药细胞中丧失。此外，我们已经表明，在药物敏感细胞中对MCJ表达的抑制会在体外诱导对特定药物（紫杉醇，阿霉素）的抗性。在我们最初的资助应用程序（CA127099）中，我们提出的是，乳腺肿瘤中MCJ表达的丧失通过1）使用免疫缺陷小鼠中人类乳腺癌细胞系的异种移植模型（AIM 1）和2）发电MCJ敲除小鼠来破坏MCJ在小鼠Mammmary Mammary Mammary（AIM 2）中促进多药的耐药性。另一个重要的问题是，乳腺癌细胞中的MCJ表达是否可以视为乳腺癌患者化学疗法反应的预测标记。为了响应该通知，NOD-09-058的标题为“ NIH宣布竞争性修订申请的恢复ACT资金的可用性”，我们现在要求对当前赠款进​​行修订，以进行一项试点研究，其中我们将检查MCJ在乳腺癌患者的肿瘤组织中的表达。由于先前没有发表的研究检查了乳腺肿瘤中的MCJ，因此该修订应用的目的是找到在分类的乳腺癌患者组中表达或缺乏MCJ的相对频率，以及找到MCJ表达与不同临床参数的相互作用。此基本信息对于在接受特定化疗治疗的患者中研究MCJ的大型临床研究的设计和启动至关重要。该项目与人类健康高度相关，特别是在癌症治疗领域。 公共卫生相关性：乳腺癌是人类中最常见的癌症之一，也是美国女性与癌症有关的第二大癌症。化学疗法仍然是治疗乳腺癌的常见手段，但是初始反应后的无反应者和失败的百分比仍然相对较高。可以向患者提供几种化学治疗药物或药物的组合，但是没有生物学标记可以帮助预测哪些患者可能会或可能不会对特定的化学治疗方案做出反应。因此，通过使用标准临床测定法确定化学疗法的这些预测标记非常重要。预测给定化疗方案失败的生物标记物将有助于节省患者的时间，精力和不合理的疼痛。在这些情况下，可以提供替代疗法。我们最近的研究表明，MCJ是在药物敏感乳腺癌细胞系中存在的分子，但在多药耐药性乳腺癌细胞中不存在。我们还表明，在人类乳腺癌细胞系中阻止MCJ的表达大大增加了这些细胞在体外对特定化学治疗药物的抗性。因此，我们假设MCJ可以用作对这些药物反应的预测标记。在此应用中，我们建议进行一项试验研究，研究乳腺肿瘤样品中MCJ表达的表达，以表征MCJ在不同类型的乳腺癌中的总体分布。从这些研究中获得的信息将是开始大型临床研究的基础，以表明乳腺肿瘤中缺乏MCJ是否表明对蒽环素和/或紫杉烷的反应不佳。考虑到对癌症中化学疗法反应生物标志物的强烈需求，该项目与人类健康高度相关。

项目成果

Ikaros mediates the DNA methylation-independent silencing of MCJ/DNAJC15 gene expression in macrophages.

• DOI: 10.1038/srep14692
• 发表时间: 2015-09-30
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Navasa N;Martin-Ruiz I;Atondo E;Sutherland JD;Angel Pascual-Itoiz M;Carreras-González A;Izadi H;Tomás-Cortázar J;Ayaz F;Martin-Martin N;Torres IM;Barrio R;Carracedo A;Olivera ER;Rincón M;Anguita J
• 通讯作者: Anguita J