Extracellular Hsp70 and hyperthermia in tumor therapy

肿瘤治疗中的细胞外 Hsp70 和热疗

基本信息

批准号：
7880266
负责人：
STUART Keith CALDERWOOD
金额：
$ 31.59万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-21 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880266
关键词：
Adaptor Signaling Protein Affinity Antigen-Presenting Cells Antigens Apoptosis Binding Binding Proteins Breast Cancer Cell Breast Cancer Treatment Breast Carcinoma Cessation of life Complex Cytoplasm Cytotoxic Chemotherapy Data Development Effector Cell Equilibrium Family member Fever Gap Junctions Genes Genetic Transcription Goals Growth Heat shock proteins Heat-Shock Proteins 70 Heat-Shock Response Heregulin Immune Immunization Laboratories Malignant Neoplasms Maps Measures Mediating Neoplasm Metastasis Oncogenic Pathway interactions Patients Peptides Phagocytosis Phosphoproteins Play Process Protein Dephosphorylation Protein Family Protein Kinase Proteins Proto-Oncogenes Regulation Role Serine Signal Pathway Signal Transduction Stimulus Surface Surface Antigens Surface Plasmon Resonance TLR2 gene Testing Transcriptional Activation Vaccines adaptive immunity base cell growth design extracellular gene repression heat shock transcription factor human tissue immune activation malignant breast neoplasm neoplastic cell novel strategies overexpression prognostic indicator receptor receptor binding receptor expression response scavenger receptor tumor tumor growth tumor immunology

项目摘要

DESCRIPTION (provided by applicant): Heat shock proteins (Hsp) have emerged as significant factors in the development of a number of cancers. One of the long-term aims of our laboratory is to assess the role of these Hsp in breast cancer malignancy and to progress towards targeting them in therapy. This application, is aimed at study of heat shock transcription factor 1 (HSF1), the protein which activates hsp gene transcription. We aim to study the mechanisms underlying the overexpression and activation of HSF1 in breast cancer. Our hypothesis is that HSF1 is the downstream target of a signaling pathway that is initiated by interaction of the oncogenic factor heregulin with the proto-oncogene HER2/c-erb-b2 on the surface on breast cancer cells. This leads to deactivation of the protein kinase GSK3 and to dephosphorylation of HSF1 on an inhibitory serine residue (Ser303). We aim to show that S303 dephosphorylation blocks inhibitory interactions of HSF1 with the phosphoprotein binding proteins 14-3-3 and SCFFbw7 and thus leads to HSF1 activation. We then aim to determine the effects of HSF1 activation in the growth and malignancy of breast cancer cells. We will first examine whether the transcriptional activation of hsp gene by HSF1 leads to inhibition of programmed cell death (PCD) in breast cancer cells exposed to heregulin. Such a decrease would increase tumor growth by upsetting the balance between cell growth and death and would also inhibit the effects of cytotoxic therapies in breast cancer treatment. Another consequence of HSF1 elevation is the enhanced transcriptional repression of genes that deter invasion and metastasis. We aim to examine the role of HSF1 in binding to the gene co- repressor metastasis associated protein 1 (MTA1) in gene repression in breast cancer. We will finally assess the rate at which changes in expression of HSF1, Hsps and MTA1 occur in breast carcinoma tissues from human patients. Our ultimate goals are (1) to use the data derived from mechanistic studies of HSF1 and its interacting proteins to design novel approaches to treating breast carcinoma and (2) to assess HSF1 and HSF1/MTA1 ratios as prognostic indicators of breast cancer response to therapy.

描述（由申请人提供）：热休克蛋白（Hsp）已成为多种癌症发展的重要因素。我们实验室的长期目标之一是评估这些热休克蛋白在乳腺癌恶性肿瘤中的作用，并在靶向治疗中取得进展。该应用旨在研究热休克转录因子 1 (HSF1)，即激活 hsp 基因转录的蛋白质。我们的目标是研究乳腺癌中 HSF1 过度表达和激活的机制。我们的假设是，HSF1 是信号通路的下游靶标，该信号通路是由致癌因子调蛋白与乳腺癌细胞表面的原癌基因 HER2/c-erb-b2 相互作用启动的。这会导致蛋白激酶 GSK3 失活，并导致 HSF1 在抑制性丝氨酸残基 (Ser303) 上去磷酸化。我们的目的是证明 S303 去磷酸化可阻断 HSF1 与磷蛋白结合蛋白 14-3-3 和 SCFFbw7 的抑制性相互作用，从而导致 HSF1 激活。然后我们的目标是确定 HSF1 激活对乳腺癌细胞生长和恶性的影响。我们将首先检查 HSF1 对 hsp 基因的转录激活是否会导致暴露于调蛋白的乳腺癌细胞的程序性细胞死亡（PCD）受到抑制。这种减少会通过破坏细胞生长和死亡之间的平衡来增加肿瘤的生长，并且还会抑制细胞毒性疗法在乳腺癌治疗中的效果。 HSF1升高的另一个后果是阻止侵袭和转移的基因的转录抑制增强。我们的目的是研究 HSF1 在与基因共阻遏物转移相关蛋白 1 (MTA1) 结合中在乳腺癌基因抑制中的作用。我们最终将评估人类患者乳腺癌组织中 HSF1、Hsps 和 MTA1 表达变化的发生率。我们的最终目标是 (1) 使用 HSF1 及其相互作用蛋白的机制研究数据来设计治疗乳腺癌的新方法，以及 (2) 评估 HSF1 和 HSF1/MTA1 比率作为乳腺癌治疗反应的预后指标。