Dietary intervention of non-classical Wnt signaling

非经典 Wnt 信号传导的饮食干预

• 批准号: 9240612
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240612
• 关键词: Antineoplastic Agents; 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; Etiology; Event; Extracellular Matrix; Family; Gatekeeping; Gene Targeting; Growth; Homeostasis; Intervention; 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; cancer cell; chemo-dietary; chemokine; cost; cytokine; defined contribution; feeding; 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（由适用提供）：由于相关的治疗性，疾病的缓解和死亡率，乳腺癌的侵入性和转移性性质构成了巨大的挑战。癌细胞的行为取决于它们与周围组织的相互作用。骨桥蛋白（OPN）是乳腺基质的关键组成部分。 OPN在超过70％的恶性乳腺癌病例中过表达，其过表达表明预后不良。 OPN潜在细胞的恶性特性，特别是通过促进其成长，侵袭和转移的能力。 Wnt信号在乳腺癌中失调。我们还证明了WNT稳态的错过导致EMT激活和恶性进展。我们还证明了HSP40伴侣家族的成员DNAJB6会干扰Wnt/β-catenin信号传导，实际上，DNAJB6是EMT的守门人，导致转移降低。在乳腺癌的侵入性进展中，DNAJB6蛋白表达受到损害。 DNAJB6表达的丧失是促进肿瘤细胞分泌OPN的关键因素之一。该提案的中心假设是OPN激活了无独立的非经典β-链氨酸信号传导，导致乳腺癌的恶性进展。这种非古典激活的β-链氨酸活性与 关于肿瘤进展，多药耐药性以及在诊所测试的WNT抑制剂。基于关于其抵消Wnt信号传导能力并恢复DNAJB6表达的令人信服的观察结果，我们建议测试饮食中的类黄酮，fisetin，用于逆转或预防EMT和对药物治疗的耐药性。 Fisetin基本上存在于芒果，草莓等中，因此是一种负担得起的饮食补充方式。我们的目标是（i）表征β-catenin信号传导非古典激活和（ii）的机制和作用，以确定鱼片是否是依赖EMT和预防转移的有效功能性食物。我们还将测试Fishin对提高乳腺癌细胞对细胞毒性化疗的敏感性的影响。结果将允许将鱼类用作饮食干预措施来阻止因肿瘤微环境中OPN引起的非古典β-catenin信号传导。这项工作还将测试预防策略，以干预乳腺癌的转移性传播。影响：考虑到正在进行的临床试验对抑制WNT信号传导的重点，拟议的工作将立即影响正在进行的临床试验。这项研究有可能补充昂贵和使人衰弱的化学疗法方案。