Dietary intervention of non-classical Wnt signaling

非经典 Wnt 信号传导的饮食干预

• 批准号: 9889045
• 负责人: Rajeev S Samant
• 金额: $ 33.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889045
• 关键词: Automobile Driving; Behavior; Breast; Breast Cancer Cell; Cell Polarity; Cell Proliferation; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Trials; Complement; Cytotoxic Chemotherapy; Data; Dietary Flavonoid; Dietary Intervention; Dietary Supplementation; Disease Progression; Drug resistance; Embryonic Development; Epithelial; Epithelium; Etiology; Event; Extracellular Matrix; Family; Gatekeeping; Genes; Growth; Homeostasis; Invaded; Laboratories; Ligands; Lung; Malignant - descriptor; Mammary Neoplasms; Mango - dietary; Mesenchymal; Metastatic to; Molecular; Molecular Chaperones; Molecular Target; Multi-Drug Resistance; Nature; Neoplasm Metastasis; Outcome; Pathway interactions; Pharmacotherapy; Phenotype; Play; Porcupines; Prevention strategy; Property; Publishing; Recurrent disease; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Site; Strawberries; Stromal Cells; TCF Transcription Factor; Testing; Tissues; Transcriptional Activation; Treatment Efficacy; WNT Signaling Pathway; Work; base; beta catenin; bone; breast cancer progression; cancer cell; cancer drug resistance; chemo-dietary; chemokine; cost; cytokine; defined contribution; fisetin; functional food; improved; inhibitor/antagonist; malignant breast neoplasm; member; mortality; neoplastic cell; novel; osteopontin; outcome forecast; overexpression; prevent; protein expression; public health relevance; targeted agent; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): The invasive and metastatic nature of breast cancer poses a formidable challenge due to the associated therapeutic resistance, disease relapse and mortality. The behavior of cancer cells is dictated by their interaction with their surrounding tissue. Osteopontin (OPN) is a critical component of breast stroma. OPN is overexpressed in over 70% cases of malignant breast neoplasms and its overexpression is indicative of poor prognosis. OPN potentiates malignant properties of cells, specifically by promoting their ability to grow, invade, and metastasize. Wnt signaling is dysregulated in breast cancer. We showed that mis-regulation of Wnt homeostasis results in EMT activation and malignant progression. We also demonstrated that DNAJB6, a member of HSP40 family of chaperones, interferes with Wnt/β-catenin signaling and in fact, acts as a gatekeeper of EMT resulting in reduced metastasis. In invasive progression of breast cancer, DNAJB6 protein expression is compromised. Loss of DNAJB6 expression is one of the key factors that promote secretion of OPN by the tumor cells. The central hypothesis of this proposal is that OPN activates Wnt-ligand independent, non-classical β- catenin signaling, leading to malignant progression of breast cancer. This non-classical activation of β- catenin activity has profound implications with respect to tumor progression, multi-drug resistance and importantly to Wnt inhibitors being tested in the clinic. Based on compelling observations regarding its ability to counteract Wnt signaling, and restore DNAJB6 expression, we propose to test the dietary flavonoid, fisetin for reversing or preventing EMT and resistance to drug treatment. Fisetin is abundantly present in mangos, strawberries etc. and thus are an affordable means of dietary supplementation. Our objectives are (i) To characterize the mechanisms and effects of non-classical activation of β-catenin signaling and (ii) To determine if fisetin serves as an effective functional food to revere EMT and prevent metastasis. We will also test fisetin's impact on improving sensitivity of breast cancer cells to cytotoxic chemotherapy. The outcome will allow use of fisetin as a dietary intervention to block non-classical β-catenin signaling due to OPN in the tumor microenvironment. The work will also test prevention strategies to intervene in metastatic dissemination of breast cancer. Impact: Considering the emphasis of ongoing clinical trials on inhibition of Wnt signaling, the proposed work will have immediate impact on the course of ongoing clinical trials. This research has the potential to complement costly and debilitating chemotherapy regimens.

 描述(由申请人提供)：乳腺癌的侵袭性和转移性是一个巨大的挑战，因为相关的治疗抵抗，疾病复发和死亡率。癌细胞的行为是由它们与周围组织的相互作用决定的。骨桥蛋白(OPN)是乳腺间质的重要成分。OPN在70%以上的恶性乳腺肿瘤中过度表达，其过度表达提示预后不良。OPN增强了细胞的恶性特性，特别是通过促进其生长、侵袭和转移的能力。WNT信号在乳腺癌中的表达失调。我们发现Wnt动态平衡的错误调节导致了EMT的激活和恶性进展。我们还证明了DNAJB6是Hsp40分子伴侣家族中的一员，它干扰Wnt/β-catenin信号转导，事实上，它在子宫内膜癌中起着守门人的作用，从而减少转移。在乳腺癌的侵袭性进展中，DNAJB6蛋白的表达受到影响。DNAJB6表达缺失是促进肿瘤细胞分泌骨桥蛋白的关键因素之一。这一建议的中心假设是骨桥蛋白激活非经典的β-连环蛋白信号，导致乳腺癌的恶性进展。这种β-连环蛋白活性的非经典激活具有深远的意义 在肿瘤进展、多药耐药以及更重要的是在临床上测试Wnt抑制剂方面。基于对其对抗Wnt信号和恢复DNAJB6表达能力的令人信服的观察，我们建议测试饮食中的类黄酮非瑟丁逆转或预防EMT和耐药治疗的作用。非瑟素在芒果、草莓等水果中含量丰富，因此是一种负担得起的饮食补充方式。我们的目标是(I)研究非经典激活β-连环蛋白信号的机制和作用，以及(Ii)确定非瑟素是否作为一种有效的功能食品来逆转子宫内膜样变和防止转移。我们还将测试非瑟素在提高乳腺癌细胞对细胞毒化疗敏感性方面的影响。结果将允许使用非瑟素作为饮食干预，以阻断由于肿瘤微环境中的骨桥蛋白而产生的非经典β-连环蛋白信号。这项工作还将测试干预乳腺癌转移扩散的预防策略。影响：考虑到正在进行的临床试验的重点是抑制Wnt信号，拟议的工作将对正在进行的临床试验的过程产生直接影响。这项研究有可能补充昂贵和虚弱的化疗方案。

项目成果

Emerging roles and underlying molecular mechanisms of DNAJB6 in cancer.

• DOI: 10.18632/oncotarget.9803
• 发表时间: 2016-08-16
• 期刊: Oncotarget
• 作者: Meng E;Shevde LA;Samant RS
• 通讯作者: Samant RS