Interplay between ER and TGF-b in carcinogenesis

雌激素受体与转化生长因子-β在肿瘤发生中的相互作用 靶向治疗使包括乳腺癌在内的各种癌症的生存率提高。一 靶向治疗的关键挑战是耐药性和复发的发展。 因此，识别代偿途径激活的潜在机制， 迫切需要进一步开发协同靶向治疗的新药剂。 该提案旨在确定KLF 4（Krüppel样因子4）蛋白水解的影响， 在乳腺肿瘤发生/侵袭中协调由雌激素或TGF-β启动的信号传导， 以及对内分泌治疗的抵抗力。我们和其他人最近的研究表明，KLF 4 成为调节雌激素受体信号和TGF-β信号的新参与者 途径，并且其失调导致肿瘤发生和耐药性。我们 研究表明，在雌激素的作用下，KLF 4的表达上调，这是由于KLF 4的抑制。 由E3连接酶VHL/VBC控制的KLF 4周转促进雌激素诱导的促有丝分裂 增长我们还观察到，在对他莫昔芬耐药的乳腺癌细胞中， KLF 4由于KLF 4降解的抑制，这是由于 致癌TGF-β信号传导减弱他莫昔芬反应。我们进一步观察到， β-TRCP/SCF通过破坏KLF 4水平介导雌激素反应 TGF-β激活Src的E3连接酶VHL，通过促进KLF 4的表达，诱导KLF 4的积累。 VHL的降解，这反过来又拮抗他莫昔芬反应。的目的 该项目旨在确定泛素-蛋白酶体系统调节 雌激素诱导的KLF 4积累，确保雌激素反应， 通过代偿性TGF-β激活Src， 抑制VHL介导的KLF 4降解。此应用程序的最终目标是 确定KLF 4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，并进一步验证我们的新的治疗干预， 开发了KLF 4抑制剂来挽救他莫昔芬耐药性。我们的具体目标是 （1）确定泛素降解机制如何协调雌激素- 诱导KLF 4蓄积;（2）确定KLF 4-VHL/VBC轴的失调如何影响KLF 4-VHL/VBC轴的表达。 导致癌症干细胞的自我更新增强，乳腺肿瘤发生/进展， 有助于抗雌激素抵抗;和（3）确定对雌激素受体的调节失调的影响。 KLF 4-VHL/VBC轴在乳腺肿瘤发生/侵袭中的作用，并验证其治疗作用。 KLF 4抑制剂干预抗雌激素抵抗小鼠模型的救援。

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.