BBOX1 is a Novel Oncogenic Driver in Triple Negative Breast Cancer

BBOX1 是三阴性乳腺癌的新型致癌驱动因素

基本信息

批准号：
10577757
负责人：
Qing Zhang
金额：
$ 38.72万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577757
关键词：
3-Dimensional Affect Agar Anabolism Binding Biochemical Reaction Biological Assay Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Breast Epithelial Cells Calcium Calcium Channel Calcium Signaling Carnitine Cell Proliferation Cells Clinical Custom D Cells DNA Data Defect Development Disease Distant Metastasis ERBB2 gene Endoplasmic Reticulum Enzyme Inhibitor Drugs Enzymes Epithelial Cell Proliferation Family Family member Foundations Genetic Glycolysis Growth Hydroxylation Hypoxia ITPR1 gene Impairment In Vitro Inositol Levocarnitine Libraries Malignant Neoplasms Mediating Metabolism Mitochondria Mixed Function Oxygenases Molecular Oncogenic Oxygen Pathogenesis Pathway interactions Patient-derived xenograft models of breast cancer Patients Phenotype Process Procollagen-Proline Dioxygenase Prognosis Proteins Recording of previous events Reporting Respiration Role Signal Transduction Small Interfering RNA Testing Therapeutic Tissue Microarray Ubiquitination Xenograft Model alpha ketoglutarate carcinogenesis cell growth clinically relevant efficacy testing experimental study fitness histone demethylase in vivo inhibitor inorganic phosphate knock-down malignant breast neoplasm mortality new therapeutic target novel novel therapeutics orthotopic breast cancer overexpression patient derived xenograft model pharmacologic prevent receptor screening therapeutic target triple-negative invasive breast carcinoma tumor growth tumor metabolism tumorigenesis

项目摘要

Project Summary Triple-Negative breast cancer (TNBC), which accounts for 15-20% of all breast cancer, represents an aggressive clinical history, development of distant metastasis, shorter survival and high mortaility rate compared with other subtypes of breast cancer. It is imperative to identity new therapeutic targets that are actionale in TNBC. Our lab has been focusing on studying a family of enzymes that uses oxygen, Fe2+ and 2-oxoglutarate (2-OG) for their enzymatic reactions. This enzyme family has been reported to be involved in the pathogenesis of cancers. We generated the custom siRNA library for all of 2-OG dependent enzymes and developed a stringent screening strategy by combining the functional readouts from both 2-D cell proliferation and 3-D soft agar growth assay with TNBC breast cancer cell lines. Our preliminary data show that gamma-butyrobetaine hydroxylase 1 (BBOX1) involved in carnitine biosynthesis pathway is essential for TNBC cell proliferation on 2-D and 3-D. Mechanistically, we show that BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3), therefore promoting calcium release, mitochondrial function and glycolysis in TNBC. We hypothesize that BBOX1-IP3R3 signaling axis promotes TNBC by inducing calcium release and tumor metabolism. This is the first study directed at a pro-oncogenic function for BBOX1 in cancer, with our focus in TNBC. In Specific Aim 1, we will characterize the functional significance of BBOX1-IP3R3 signaling in TNBC. In Specific Aim 2, we will elucidate the molecular mechanism by which BBOX1-IP3R3 signaling promotes oncogenic phenotypes in TNBC. In Specific Aim 3, we will assess the therapeutic implications of targeting BBOX1 in TNBC xenografts and patient derived xenografts (PDXs). Successful completion of this proposal would establish the role of BBOX1 as a new oncogenic driver in TNBC and explore its therapeutic potential in this lethal disease.

项目概要三阴性乳腺癌 (TNBC) 占所有乳腺癌的 15-20%，是一种侵袭性乳腺癌。与其他疾病相比，临床病史、发生远处转移、生存期短、死亡率高乳腺癌的亚型。确定可用于 TNBC 的新治疗靶点势在必行。我们的实验室一直致力于研究利用氧、Fe2+和2-氧戊二酸（2-OG）的酶家族酶促反应。据报道，该酶家族参与癌症的发病机制。我们为所有 2-OG 依赖性酶生成了定制 siRNA 文库，并开发了严格的筛选通过结合 2-D 细胞增殖和 3-D 软琼脂生长测定的功能读数来制定策略 TNBC 乳腺癌细胞系。我们的初步数据表明，γ-丁甜菜碱羟化酶 1 (BBOX1) 参与肉碱生物合成途径，对于 TNBC 细胞的 2-D 和 3-D 增殖至关重要。从机制上讲，我们表明 BBOX1 与钙通道肌醇-1,4,5-三磷酸受体结合 3 型 (IP3R3)，因此促进 TNBC 中的钙释放、线粒体功能和糖酵解。我们假设 BBOX1-IP3R3 信号轴通过诱导钙释放和肿瘤促进 TNBC 代谢。这是第一项针对 BBOX1 在癌症中的促癌功能的研究，我们的重点是 TNBC。在具体目标 1 中，我们将描述 BBOX1-IP3R3 信号传导在 TNBC 中的功能意义。在具体目标2，我们将阐明BBOX1-IP3R3信号传导促进的分子机制 TNBC 中的致癌表型。在具体目标 3 中，我们将评估靶向治疗的治疗意义 TNBC 异种移植物和患者来源的异种移植物 (PDX) 中的 BBOX1。该提案的顺利完成将确定 BBOX1 作为 TNBC 中新的致癌驱动因素的作用，并探索其在这种致命疾病中的治疗潜力疾病。