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: 9512889
• 负责人: Yong Wan
• 金额: $ 12.2万
• 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/9512889
• 关键词: Address; Apoptosis; Attenuated; Automobile Driving; Breast Cancer Cell; Breast Carcinogenesis; Cell division; Cells; DNA Damage; Data; Development; Drug resistance; Drug usage; Ensure; Estrogen Antagonists; Estrogen Receptors; Estrogens; Exhibits; GKLF protein; Goals; Growth; Human; Lead; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Molecular; New Agents; Oncogenic; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Proteolysis; Receptor Signaling; Recurrence; Regulation; Regulation of Proteolysis; Resistance; Role; Signal Transduction; System; TGF Beta Signaling Pathway; Tamoxifen; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Transforming Growth Factor beta; Tumor Cell Invasion; Ubiquitin; Up-Regulation; Xenograft procedure; beta-Transducin Repeat-Containing Proteins; cancer stem cell; carcinogenesis; clinically relevant; drug development; hormone therapy; in vivo; inhibitor/antagonist; malignant breast neoplasm; mouse model; multicatalytic endopeptidase complex; neoplastic cell; novel; novel strategies; response; self-renewal; targeted treatment; tumor; tumor initiation; tumor progression; tumorigenesis; ubiquitin-protein ligase

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在癌变中的相互作用 有针对性的疗法使包括乳腺癌在内的各种癌症受益。一个 靶向疗法的关键挑战是耐药性和复发的发展。 那就是鉴定代偿途径激活的基础机制和 迫切需要进一步开发与目标疗法协同作用的新药物。 该建议旨在确定KLF4（Krüppel样因子4）蛋白水解的影响， 策划雌激素或TGF-β在乳腺肿瘤倡议/侵袭中发起的信号，AS 以及对内分泌疗法的抵抗。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传导以及TGF-β信号的新型玩家 途径，其放松管制导致肿瘤发生和耐药性。我们 证明在响应雌激素时，由于抑制了KLF4的上调 由E3连接酶VHL/VBC最爱雌激素诱导的有丝分裂的KLF4周转率 生长。我们还观察到在他莫昔芬耐药的乳腺癌细胞中积累 KLF4由于KLF4降解的抑制，由于补偿性激活 致癌TGF-β信号传导减弱了他莫昔芬的反应。我们进一步观察到 β-TRCP/SCF通过破坏KLF4水平的升高来介导雌激素反应 在其E3连接酶VHL中，TGF-β激活的SRC诱导KLF4的积累，通过促进 VHL的降解又使他莫昔芬反应拮抗。这个目的 项目旨在确定泛素 - 蛋白酶体系统调节的机制 雌激素诱导的KLF4积累，可确保雌激素反应，然后 通过代偿性TGF-β激活SRC，抵消了他莫昔芬的反应 抑制VHL介导的KLF4降解。该应用程序的最终目标是 确定KLF4蛋白水解调节在乳腺肿瘤开始/侵袭中的临床相关性 和抗雌激素的耐药性，并进一步验证我们新近的治疗干预措施 开发的KLF4抑制剂在挽救了他莫昔芬的耐药性中。我们的具体目标是 以下：（1）确定泛素降解机械如何协调雌激素 - 诱导KLF4积累； （2）确定KLF4-VHL/VBC轴的失调 导致癌症干细胞的自我更新，乳腺肿瘤的启动/进展和 有助于抗雌激素的耐药性； （3）确定放松管制的影响 乳腺肿瘤开始/入侵中的KLF4-VHL/VBC轴，并验证治疗性 KLF4抑制剂在使用鼠模型中拯救抗雌激素的耐药性中的干预。