Interplay between ER and TGF-b in carcinogenesis

雌激素受体和转化生长因子-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存活率有所提高。一个 靶向治疗的关键挑战是耐药性和复发的发展。 因此，确定激活代偿通路和 迫切需要进一步开发新的药物来协同靶向治疗。 该提案旨在确定KLF4(Krüppel-like factor4)蛋白降解的影响 协调雌激素或转化生长因子-β在乳腺肿瘤起始/侵袭中启动的信号转导，AS 以及对内分泌治疗的抵抗力。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和转化生长因子-β信号的新角色 途径，以及其放松管制导致肿瘤形成和耐药性。我们 研究表明，在对雌激素的反应中，KLF4的上调是由于抑制 受E3连接酶VHL/VBC调控的KLF4周转促进雌激素诱导的有丝分裂 成长。我们还观察到，在对他莫昔芬耐药的乳腺癌细胞中， KLF4由于补偿激活而抑制KLF4的降解 致癌的转化生长因子-β信号减弱他莫昔芬的反应。我们进一步观察到，虽然 β-TRCP/SCF通过破坏KLF4水平介导雌激素反应 在其E3连接酶VHl中，转化生长因子-β激活的Src通过促进KLF4的积累而诱导KLF4的积累 VHL的降解，进而拮抗他莫昔芬的反应。这样做的目的是 项目是确定泛素-蛋白酶体系统调节的机制 雌激素诱导的KLF4积聚，确保雌激素反应，并通过它 补偿性转化生长因子-β激活sRc通过以下途径抵消他莫昔芬的反应 抑制VHL介导的KLF4降解。此应用程序的最终目标是 确定KLF4蛋白降解调节在乳腺肿瘤起始/侵袭中的临床意义 和抗雌激素耐药，并进一步验证我们新的治疗干预 开发KLF4抑制剂以挽救他莫昔芬耐药性。我们的具体目标是 以下：(1)确定泛素降解机制如何协调雌激素- 诱导KLF4积聚；(2)确定KLF4-VHL/VBC轴的失调 导致增强癌症干细胞的自我更新，乳腺癌的启动/进展，以及 有助于抵抗雌激素；以及(3)确定放松管制对 KLF4-VHL/VBC轴在乳腺癌发生/侵袭中的作用及疗效验证 KLF4抑制剂对小鼠抗雌激素抵抗的干预作用。

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.