Extracellular Hsp70 and hyperthermia in tumor therapy

描述（由申请人提供）：热休克蛋白（Hsp）已成为许多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，并在治疗中针对它们取得进展。本应用程序旨在研究热休克转录因子1 (HSF1)，一种激活热休克基因转录的蛋白。我们的目的是研究HSF1在乳腺癌中过度表达和激活的机制。我们的假设是HSF1是一个信号通路的下游靶点，该信号通路是由致癌因子heregulin与乳腺癌细胞表面的原癌基因HER2/c- erbb -b2相互作用启动的。这导致蛋白激酶GSK3失活和HSF1在抑制丝氨酸残基（Ser303）上的去磷酸化。我们的目的是证明S303去磷酸化阻断HSF1与磷酸化蛋白结合蛋白14-3-3和SCFFbw7的抑制相互作用，从而导致HSF1活化。然后我们的目标是确定HSF1激活在乳腺癌细胞生长和恶性肿瘤中的作用。我们将首先研究HSF1对hsp基因的转录激活是否会抑制暴露于heregulin的乳腺癌细胞的程序性细胞死亡（PCD）。这种减少会打破细胞生长和死亡之间的平衡，从而增加肿瘤的生长，还会抑制细胞毒性疗法在乳腺癌治疗中的效果。HSF1基因升高的另一个后果是抑制侵袭和转移基因的转录抑制增强。我们的目的是研究HSF1在乳腺癌基因抑制中与基因共抑制因子转移相关蛋白1 （MTA1）结合的作用。我们将最终评估HSF1、Hsps和MTA1在人类乳腺癌组织中的表达变化率。我们的最终目标是：(1)利用HSF1及其相互作用蛋白的机制研究得出的数据来设计治疗乳腺癌的新方法；(2)评估HSF1和HSF1/MTA1比率作为乳腺癌治疗反应的预后指标。

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.