The role of tristetraprolin in control of breast cancer progression

描述（由申请人提供）：肿瘤细胞中促肿瘤因子（如细胞因子和脂质分子）的表达在肿瘤生长和转移中起关键作用。然而，肿瘤细胞产生这些因子的机制在很大程度上仍然是未知的。最近，我们已经发现，表达tristetraprolin（TTP），锌指蛋白促进许多靶基因的mRNA衰变，是显着减少乳腺肿瘤和肿瘤细胞。更重要的是，TTP缺陷型小鼠在小鼠乳腺肿瘤模型中显示转移增加和存活减少。因此，我们推测乳腺肿瘤细胞中受损的TTP表达通过增强肿瘤促进因子的表达来促进肿瘤转移。TTP可能成为乳腺癌治疗的新靶点。TTP是CCCH串联锌指蛋白的成员，在转录后水平参与炎症反应的调节。TTP与3 '非翻译区（3'UTR）内的腺嘌呤-尿苷富集元件（ARE）结合，导致编码TNF-1、GM-CSF等的mRNA的不稳定。在TTP敲除小鼠中，促炎细胞因子的过度产生导致严重的全身炎症反应，包括关节炎、自身免疫和骨髓增生。总的来说，所有证据都表明TTP是一种参与控制炎症和维持稳态的关键蛋白质。我们最近发现，乳腺肿瘤中TTP表达的降低与肿瘤微环境中Th17细胞的增加和IL-23表达的增强相关。IL-23通过促进肿瘤生长和转移在肿瘤进展中发挥重要作用。我们的数据首次表明乳腺肿瘤细胞可以像巨噬细胞和DC一样分泌IL-23。此外，TTP在乳腺肿瘤细胞中的过表达抑制了IL-23的表达.由于乳腺癌细胞中IL-23表达增强和TTP表达降低的分子机制尚不清楚，因此本研究拟：（1）探讨TTP抑制乳腺癌细胞IL-23表达的分子机制和信号通路;（2）确定调节乳腺癌细胞中TTP表达的分子机制;（3）评价靶向IL-23和TTP在肿瘤细胞中表达对乳腺肿瘤生长和转移的治疗作用。我们的长期目标是阐明TTP抑制乳腺肿瘤进展的细胞、分子和免疫学机制，并最终开发出能够以肿瘤特异性方式重建乳腺肿瘤中TTP表达的治疗方法，作为一种新的乳腺癌治疗方法。 公共卫生相关性： 肿瘤细胞表达肿瘤促进因子对肿瘤的生长和转移起关键作用。我们推测乳腺肿瘤细胞中受损的tristetraprolin（TTP）表达通过增强肿瘤促进因子的表达来促进肿瘤转移。我们的目标是阐明TTP抑制乳腺肿瘤进展的细胞、分子和免疫学机制，并最终开发出能够以肿瘤特异性方式重建乳腺肿瘤中TTP表达的治疗方法，作为一种新的乳腺癌治疗方法。

DESCRIPTION (provided by applicant): Expression of tumor-promoting factors such as cytokines and lipid molecules from tumor cells play critical roles in tumor growth and metastasis. However, the mechanisms by which tumor cells produce these factors are still largely unknown. Recently, we have found that the expression of tristetraprolin (TTP), a zinc finger protein promoting mRNA decay of many target genes, is markedly reduced in breast tumors and tumor cells. More importantly, TTP deficient mice show increased metastases and reduced survival in a mouse mammary gland tumor model. Therefore, we hypothesize that the impaired TTP expression in breast tumor cells promotes tumor metastases via enhancing expression of tumor-promoting factors. TTP may serve as a novel therapeutic target for breast cancer treatment. TTP is a member of CCCH tandem zinc finger proteins and involved in the regulation of inflammatory responses at the post-transcriptional level. TTP binds to adenine-uridine-rich elements (AREs) within the 3' untranslated region (3'UTR) causing destabilization of mRNAs encoding TNF-1, GM-CSF, et al. Overproduction of the proinflammatory cytokines in TTP knockout mice results in a severe systemic inflammatory response including arthritis, autoimmunity and myeloid hyperplasia. Collectively, all evidence indicates that TTP is a critical protein involved in the control of inflammation and maintenance of homeostasis. We recently found that the reduced TTP expression in breast tumors was correlated with increased Th17 cells and enhanced IL-23 expression in the tumor microenvironment. IL-23 has been shown to play an important role in tumor progression by promoting tumor growth and metastasis. Our data indicate for the first time that breast tumor cells could behave like macrophage and DCs to secrete IL-23. In addition, over- expression of TTP in breast tumor cells suppressed IL-23 expression. Since the molecular mechanisms of the enhanced IL-23 and reduced TTP expression in breast tumor cells are largely unknown, in this study, we propose to: (1) Investigate the molecular mechanisms and signaling pathways by which TTP inhibits IL-23 expression in breast tumor cells; (2) Identify the molecular mechanisms that regulate TTP expression in breast tumor cells; (3) Evaluate the therapeutic effects of targeting IL-23 and TTP expression in tumor cells on breast tumor growth and metastasis. Our long-term goal is to elucidate the cellular, molecular and immunologic mechanisms by which TTP suppresses breast tumor progression, and ultimately to develop therapeutic approaches that could reconstitute TTP expression in breast tumors in a tumor-specific manner as a novel breast cancer treatment. PUBLIC HEALTH RELEVANCE: Expression of tumor-promoting factors by tumor cells play critical roles for tumor growth and metastasis. We hypothesize that the impaired tristetraprolin (TTP) expression in breast tumor cells promotes tumor metastasis via enhancing expression of tumor-promoting factors. Our goal is to elucidate the cellular, molecular and immunologic mechanisms by which TTP suppresses breast tumor progression, and ultimately to develop therapeutic approaches that could reconstitute TTP expression in breast tumors in a tumor-specific manner as a novel breast cancer treatment.