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Interplay between ER and TGF-b in carcinogenesis

ER 和 TGF-b 在致癌过程中的相互作用

基本信息

批准号：
10084161
负责人：
Yong Wan
金额：
$ 8.12万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084161
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 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 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 patient derived xenograft model response self-renewal stem cell self renewal targeted treatment tumor tumor initiation tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

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.

内质网与TGF-β在癌变中的相互作用