Interplay between ER and TGF-b in carcinogenesis

ER 和 TGF-b 在致癌过程中的相互作用

• 批准号: 9655714
• 负责人: Yong Wan
• 金额: $ 26.11万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9655714
• 关键词: Interplay; between; ER; TGF; carcinogenesis

Interplay between ER and TGF-β in carcinogenesis Targeted therapies have benefited survival from various cancers, including breast cancer. A critical challenge of targeted therapies is the development of drug resistance and recurrence. Thus, identification of mechanisms underlying the activation of compensatory pathways and further development of new agents that synergize the targeted therapies are urgently needed. This proposal seeks to determine the impact of KLF4 (Krüppel-like factor 4) proteolysis that orchestrates the signaling initiated by estrogen or TGF-β in breast tumor initiation/invasion, as well as resistance to endocrine therapy. Recent studies by us and others have revealed KLF4 to be a novel player that regulates estrogen receptor signaling as well as TGF-β signaling pathways, and whose deregulation leads to tumorigenesis and drug resistance. We demonstrated that in response to estrogen, upregulation of KLF4 due to the suppression of KLF4 turnover governed by the E3 ligase VHL/VBC facilitates estrogen-induced mitogenic growth. We also observed in tamoxifen-resistant breast cancer cells that the accumulated KLF4 due to the inhibition of KLF4 degradation because of the compensatory activation of oncogenic TGF-β signaling attenuates the tamoxifen response. We further observed that while β-TRCP/SCF mediates estrogen response through the elevation of KLF4 levels by destruction of its E3 ligase VHL, TGF-β-activated Src induces accumulation of KLF4 via promoting the degradation of VHL, which in turn antagonizes the tamoxifen response. The objective of this project is to determine the mechanism by which the ubiquitin-proteasome system regulates estrogen-induced KLF4 accumulation that ensures estrogen response, and by which the activation of Src by compensatory TGF-β counteracts the tamoxifen response through suppression of VHL-mediated KLF4 degradation. The ultimate goal of this application is to identify the clinical relevance of KLF4 proteolytic regulation in breast tumor initiation/invasion and anti-estrogen resistance, and further validate the therapeutic intervention of our newly developed KLF4 inhibitor in the rescue of tamoxifen resistance. Our Specific Aims are the following: (1) to determine how the ubiquitin degradation machinery orchestrates estrogen- induced KLF4 accumulation; (2)  to determine how dysregulation of the KLF4-VHL/VBC axis leads to enhanced self-renewal of cancer stem cell, breast tumor initiation/progression, and contributes to anti-estrogen resistance; and (3) to determine the impact of deregulation of the KLF4-VHL/VBC axis in breast tumor initiation/invasion, and to validate the therapeutic intervention of KLF4 inhibitor in the rescue of anti-estrogen resistance using murine models.

ER 和 TGF-β 在致癌过程中的相互作用 靶向治疗使包括乳腺癌在内的多种癌症的生存受益。 靶向治疗的关键挑战是耐药性和复发的发展。 因此，识别补偿途径激活的潜在机制和 迫切需要进一步开发能够协同靶向治疗的新药物。 该提案旨在确定 KLF4（Krüppel 样因子 4）蛋白水解作用的影响， 在乳腺肿瘤发生/侵袭过程中协调由雌激素或 TGF-β 启动的信号传导，如 我们和其他人最近的研究揭示了 KLF4。 成为调节雌激素受体信号以及 TGF-β 信号的新型参与者 途径，其失调会导致肿瘤发生和耐药性。 证明，作为对雌激素的反应，KLF4由于抑制 由 E3 连接酶 VHL/VBC 控制的 KLF4 周转促进雌激素诱导的有丝分裂 我们还在对他莫昔芬耐药的乳腺癌细胞中观察到这种积累。 KLF4 由于补偿性激活而抑制 KLF4 降解 我们进一步观察到，致癌性 TGF-β 信号减弱了他莫昔芬的反应。 β-TRCP/SCF 通过破坏提高 KLF4 水平来介导雌激素反应 其 E3 连接酶 VHL、TGF-β 激活的 Src 通过促进 KLF4 的积累来诱导 KLF4 的积累 VHL 的降解，进而拮抗他莫昔芬的反应。 该项目的目的是确定泛素-蛋白酶体系统的调节机制 雌激素诱导的 KLF4 积累确保了雌激素反应，并由此 补偿性 TGF-β 激活 Src 可通过以下方式抵消他莫昔芬反应： 抑制 VHL 介导的 KLF4 降解 该应用的最终目标是 确定 KLF4 蛋白水解调节在乳腺肿瘤发生/侵袭中的临床相关性 和抗雌激素抵抗，并进一步验证我们新的治疗干预措施 开发 KLF4 抑制剂来挽救他莫昔芬耐药性是我们的具体目标。 以下：（1）确定泛素降解机制如何协调雌激素- 诱导 KLF4 积累；(2) 确定 KLF4-VHL/VBC 轴失调的方式 导致癌症干细胞自我更新增强、乳腺肿瘤发生/进展，以及 有助于抗雌激素抵抗；以及（3）确定放松管制的影响 KLF4-VHL/VBC 轴在乳腺肿瘤起始/侵袭中的作用，并验证治疗 使用小鼠模型干预 KLF4 抑制剂挽救抗雌激素抵抗。