Roll of Nitrous Oxide (NO) and Cyclic GMP in Cancer

一氧化二氮 (NO) 和环 GMP 在癌症中的作用

基本信息

批准号：
10513319
负责人：
FERID MURAD
金额：
--
依托单位：
VETERANS ADMIN PALO ALTO HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10513319
关键词：
Affect American Aneuploidy Animals Basement membrane Biological Biological Models Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis Cancer Control Cancer cell line Cardiovascular system Categories Cell Nucleus Cells Cyclic GMP Cyclin-Dependent Kinases DNA Repair Data Deterioration Diagnosis Distant Distant Metastasis Elements Endothelium Enzymes Epithelial Cells Extracellular Matrix G1 Phase Gene Expression Glioma Goals HDAC3 gene Histone Deacetylase Histone Deacetylase Inhibitor Human Immune Immune System Diseases Immunologic Surveillance Immunological Models Implant Individual Induction of Apoptosis Invaded Malignant Neoplasms Mediating Metastatic breast cancer Military Personnel Modeling Mus Neoplasm Circulating Cells Neoplasm Metastasis Nitric Oxide Nitrous Oxide Nuclear Translocation Organ Pathway interactions Patients Positioning Attribute Primary Neoplasm Production Proliferating Receptor Signaling Recurrence Recurrent Malignant Neoplasm Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Site Soluble Guanylate Cyclase Stromal Cells Surface TP53 gene Testing Therapeutic Time Tissues Tumor Suppression Tumor Suppressor Proteins Tumor-associated macrophages Vascular Endothelial Cell Woman active duty angiogenesis antagonist cancer cell cancer initiation cancer recurrence cancer therapy drug discovery genome-wide human tissue innovation malignant breast neoplasm migration neoplastic cell novel novel therapeutic intervention pharmacologic response triple-negative invasive breast carcinoma tumor

项目摘要

This project focuses on the problem of breast cancer metastasis and recurrence, and on a novel signaling pathway that is positioned to modulate both. The key signaling molecule is the β1 subunit of soluble guanylate cyclase (sGC), an enzyme that normally functions as a heterodimer composed of α1 and β1 subunits (termed here sGCα1 and sGCβ1). In biological models, sGCβ1, but not sGCα1, can translocate into the nucleus, where it regulates expression of p53 and specific cyclin dependent protein kinases and induces G0/G1 phase arrest. Moreover sGCβ1, but not sGCα1, markedly inhibits proliferation and colony formation of human cancer cell lines, and lengthens survival time of orthotropic implanted mice over control. In human breast cancer patients, levels of sGCβ1 (but not sGCα1) directly correlate with patient survival in authentic breast cancer patients (n =1664). The hypothesis that altered expression of sGCβ1 in tumor stroma (including epithelial cells, immune cells, and vascular endothelial cells) alters responses to niche signals and modulates breast cancer recurrence will be tested by (1) interrogating the effects of sGCβ1 expression on circulating tumor cell (CTC) cluster formation, (2) examining the role of sGCβ1 expression in modulating breast cancer recurrence arising from angiogenic dormancy, and (3) determining the ability of sGCβ1-targeted histone deacetylase signaling to reverse immune dysfunction. Successfully completed, this project will validate the importance of sGCβ1-targeted HDAC signaling against recurrence of dormant breast cancer, and point the field toward new therapeutic strategies for treating metastatic breast cancer.

该项目着重于乳腺癌转移和复发的问题，以及新的信号传导可调节两者的途径。关键信号分子是可溶性鸟烯基的β1亚基环酶（SGC），一种通常用作由α1和β1亚基组成的异二聚体的酶（称为这里SGCα1和SGCβ1）。在生物模型中，SGCβ1而不是SGCα1可以转移到核中，其中它调节p53和特异性细胞周期蛋白依赖性蛋白激酶的表达，并诱导G0/G1期停滞。此外并延长对照的正交植入小鼠的生存时间。在人类乳腺癌患者中，水平在正宗乳腺癌患者中，SGCβ1（但不是SGCα1）与患者存活直接相关（n = 1664）。假设改变了肿瘤基质中SGCβ1的表达（包括上皮细胞，免疫细胞和血管内皮细胞）改变对小众信号的反应并调节乳腺癌复发通过（1）询问SGCβ1表达对循环肿瘤细胞（CTC）簇形成的影响，（2）检查SGCβ1表达在调节血管生成引起的乳腺癌复发中的作用休眠，（3）确定SGCβ1靶向组蛋白脱乙酰基酶信号传导的能力功能障碍。成功完成，该项目将验证SGCβ1为靶向HDAC信号的重要性反对休眠乳腺癌的复发，并将现场指向治疗的新治疗策略转移性乳腺癌。