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。尽管最近使用激素或抗体为基础的治疗，化疗一直是，现在仍然是治疗乳腺癌的最有效和最广泛使用的手段之一。在早期乳腺癌中，化疗可使年复发率降低24%，死亡率降低15%。然而，初始应答后无应答者和失败者的百分比仍然相对较高，表明存在不同的耐药机制。到目前为止，没有明确的预测指标，具体的化疗反应已被采用的常规临床实践。甲基化控制的J（MCJ）蛋白是辅助分子伴侣的DnaJ蛋白家族的相对较新的成员。我们最近发现MCJ在药物敏感的乳腺癌细胞中表达，但在多药耐药细胞中失去表达。此外，我们已经表明，药物敏感细胞中MCJ表达的抑制在体外诱导对特定药物（紫杉醇、阿霉素）的抗性。在我们最初的资助申请（CA 127099）中，我们提出通过1）在免疫缺陷小鼠中使用人乳腺癌细胞系的异种移植模型（Aim 1）和2）产生MCJ敲除小鼠以破坏小鼠乳腺肿瘤中的MCJ表达（Aim 2）来证明乳腺肿瘤中MCJ表达的丧失促进体内多药耐药性。另一个重要的问题是乳腺肿瘤细胞中MCJ的表达是否可以被认为是乳腺癌患者化疗反应的预测标志物。为了响应通知NOT-OD-09-058题为“NIH宣布恢复法案资金竞争性修订申请的可用性”，我们现在要求对我们目前的拨款进行修订，以进行一项试点研究，我们将在乳腺癌患者的肿瘤组织中检查MCJ表达。由于之前没有发表的研究检查乳腺肿瘤中的MCJ，因此本修订申请的目的是发现乳腺癌患者分类组中表达或缺乏MCJ的肿瘤的相对频率，以及发现MCJ表达与不同临床参数的相互作用。这些基本信息对于设计和启动一项大型临床研究至关重要，该研究在接受特定化疗治疗的患者中检查MCJ。该项目与人类健康密切相关，特别是在癌症治疗领域。 公共卫生相关性：乳腺癌是人类最常见的癌症之一，也是美国女性癌症相关死亡的第二大原因。化疗仍然是治疗乳腺癌的常用手段，但无应答者和初始应答后失败的百分比仍然相对较高。可以向患者提供几种化疗药物或药物组合，但没有生物标志物帮助预测哪些患者可能对特定化疗方案有反应或可能没有反应。因此，通过使用标准临床测定来鉴定这些用于化疗的预测标志物是非常重要的。预测给定化疗方案失败的生物标志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是一个分子存在于药物敏感的乳腺癌细胞系，但不是在多药耐药乳腺癌细胞。我们还表明，阻断MCJ在人乳腺癌细胞系中的表达显著增加了这些细胞对体外特定化疗药物的抗性。因此，我们假设MCJ可以用作对这些药物反应的预测标志物。在本申请中，我们建议进行一项初步研究，检查MCJ在乳腺肿瘤样本中的表达，以表征MCJ在不同类型乳腺癌中的总体分布。从这些研究中获得的信息将是启动大型临床研究的基础，以显示乳腺肿瘤中缺乏MCJ是否表明对蒽环类和/或紫杉烷类药物的反应较差。考虑到对癌症化疗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