BBOX1 is a Novel Oncogenic Driver in Triple Negative Breast Cancer

项目摘要 三阴性乳腺癌（TNBC）占所有乳腺癌的15-20%，代表了侵袭性乳腺癌。 与其他化疗方案相比，化疗方案具有临床病史、远处转移、生存期短、死亡率高等特点 乳腺癌的亚型。鉴定在TNBC中有效的新治疗靶标是必要的。我们实验室 一直专注于研究一个家族的酶，使用氧，铁2+和2-酮戊二酸（2-OG）为他们的 酶反应。据报道，这种酶家族参与癌症的发病机制。我们 为所有2-OG依赖性酶生成定制的siRNA文库，并开发了严格的筛选 通过结合来自2-D细胞增殖和3-D软琼脂生长测定的功能读数的策略 TNBC乳腺癌细胞系。我们的初步数据表明，γ-丁基甜菜碱羟化酶1 在二维和三维上，参与肉毒碱生物合成途径的BBOX 1对于TNBC细胞增殖是必需的。 从机制上讲，我们发现BBOX 1与钙通道肌醇-1，4，5-三磷酸受体结合 3型（IP 3R 3），因此促进TNBC中的钙释放、线粒体功能和糖酵解。我们 假设BBOX 1-IP 3R 3信号传导轴通过诱导钙释放和肿瘤生长促进TNBC， 新陈代谢.这是第一项针对BBOX 1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，我们将表征BBOX 1-IP 3R 3信号传导在TNBC中的功能意义。在 具体目标2，我们将阐明BBOX 1-IP 3R 3信号转导促进的分子机制 TNBC中的致癌表型。在具体目标3中，我们将评估靶向治疗的意义 TNBC异种移植物和患者来源的异种移植物（PDX）中的BBOX 1。成功完成这项提案将 建立BBOX 1作为TNBC中新的致癌驱动因子的作用，并探索其在这种致命疾病中的治疗潜力。 疾病

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.