Mitochondria-nuclear crosstalk in triple negative breast cancer racial disparity

三阴性乳腺癌种族差异中的线粒体-核串扰

• 批准号: 9072188
• 负责人: Benny Abraham Kaipparettu
• 金额: $ 5.32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-24 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9072188
• 关键词: Accounting; Affect; African American; Age; Animals; Apoptotic; Benign; Bioinformatics; Biological; Biological Assay; Biometry; Breast; Breast Cancer Patient; Cancerous; Categories; Caucasians; Cell Line; Cell Nucleus; Cells; Cessation of life; Clinical; Communication; DNA; Data; Development; Diagnosis; Disease; Drug Targeting; Electron Transport; Exposure to; Foundations; Gene Chips; Generic Drugs; Genes; Growth and Development function; Health; Histones; Housing; In Vitro; Incidence; Malignant Neoplasms; Maps; Metabolic; Metastatic breast cancer; Microarray Analysis; Mitochondria; Mitochondrial DNA; Modeling; Modification; Mutation; Neoplasm Metastasis; Neoplasms; Nuclear; Oncogene Proteins; Oncogenic; Organelles; Paper; Pathway Analysis; Pathway interactions; Patients; Phenotype; Play; Post-Translational Protein Processing; Prognostic Marker; Property; Proteins; Reactive Oxygen Species; Regulation; Research; Role; SRC gene; Sampling; Sequence Analysis; Staging; System; Technology; Translating; Translations; Transplantation; Variant; Woman; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer type; chemotherapy; clinically significant; drug development; follow-up; in vivo; innovation; interest; malignant breast neoplasm; metabolomics; mitochondrial DNA mutation; mortality; next generation sequencing; novel; prevent; racial disparity; response; src-Family Kinases; triple-negative invasive breast carcinoma; tumor; tumor progression

DESCRIPTION (provided by applicant): For Triple Negative BCa (TN BCa), there is a current lack of understanding of driver pathways and hence are often treated using more generic therapies. Currently there are no clinically accepted targets for the treatment for TN BCa and to predict its potential to metastasize. while BCa incidence is higher in Caucasian (CA) women, death due to BCa is higher in African American (AA) women. Importantly, AA patients are more likely to be diagnosed with triple negative (TN) BCa and at a more advanced stage than CA. Mitochondria is considered the energy house of the cell and has been strongly implicated in tumor development and progression and thus serving as a potential target for chemotherapy. With the advent of Transmitochondrial cybrid (cybrid) technology, it is now possible to examine the specific contribution of tumor-associated mitochondria to neoplastic growth and development under a defined nuclear background. Cybrids are constructed by fusing enucleated cells harboring mitochondria of interest with ?0 recipient cells (cells harboring ablated mitochondrial DNA). Using this technology in both an in vitro and in vivo setting, we have demonstrated a key role for mitochondrial retrograde regulation (MRR) progression of TN BCa. We have also identified critical regulation of post-translational modification of Src oncogenic pathway by cancer mitochondria. Our preliminary analysis using cybrids with mitochondria from AA and CA TN BCa cell lines suggest that mitochondrial retrograde regulation (MRR) of nuclear genes are different in AA and CA cells. Here we propose to combine Dr. Kaipparettu's (PI) expertise in BCa and cybrid technology with Dr. Lewis expertize in generating patient derived xenografts and Dr. Creighton's expertise in bioinformatics to evaluate a clinically challenging question, "How can we better distinguish AA and CA TN BCa by its MRR?" Strategically, we will use cybrid system generated from AA and CA TN BCa patients-derived xenografts to analyze the mitochondria specific alterations in metastatic BCa. ?0 cells from different TN breast-derived AA and CA nuclear background are already available in Kaipparettu lab. The cybrids thus generated will be confirmed for their mitochondrial function, nuclear origin by next-gen sequencing and evaluated for phenotypic changes using in vitro and in vivo tumor forming/invasion assays. Following this, cybrids with AA and CA mitochondria will be profiled for their Src pathway modification. To identify novel pathways, the MRR of cybrids will be analyzed by microarray and the gene expression will be examined using an established biostatistics and bioinformatics pipelines (Oncomine Concept Mapping) together with the biostatistician Dr. Creighton to generate oncogenic signatures and pathways associated with AA and CA TN BCa metastasis. The nominated pathways will be evaluated for their role in TN BCa progression using cell line and xenograft models. Overall, we expect to develop the first- of-its-kind mitochondria-driven oncogenic signature for AA and CA TN BCa progression. Clinically, we expect these to be translated to identify new drug targets for AA TN BCa.

描述（由申请人提供）：对于三重负BCA（TN BCA），目前缺乏对驾驶员通路的了解，因此通常使用更多的通用疗法来治疗。当前，尚无临床接受的TN BCA治疗目标，并且可以预测其转移的潜力。虽然白种人（CA）妇女的BCA发病率较高，但非裔美国人（AA）妇女因BCA而导致的死亡较高。重要的是，与CA相比，AA患者更有可能被诊断为三重阴性（TN）BCA，并且在更先进的阶段。线粒体被认为是细胞的能量室，并且已与肿瘤的发育和进展有很大的影响，因此是化学疗法的潜在靶标。随着经膜软骨cybrid（Cybrid）技术的出现，现在有可能检查与肿瘤相关的线粒体在定义的核背景下对肿瘤生长和发育的特定贡献。 Cybrids是通过融合具有含线粒体感兴趣的含有浓缩型的含有线粒体的受体细胞（带有烧蚀的线粒体DNA的细胞）来构建的。在体外和体内环境中使用该技术，我们已经证明了TN BCA的线粒体逆行调节（MRR）进展的关键作用。我们还确定了通过癌症线粒体对SRC致癌途径翻译后修饰的批判性调节。我们使用来自AA和CA TN BCA细胞系的线粒体的Cybrids的初步分析表明，核基因的线粒体逆行调节（MRR）在AA和CA细胞中有所不同。在这里，我们建议将Kaipparettu博士（PI）在BCA和Cybrid技术方面的专业知识与Lewis博士的专业知识与Lewis博士的专业化，以生成患者衍生的异种移植物以及Creighton博士在生物信息学方面的生物信息学专业知识，以评估临床上具有挑战性的问题，“我们如何更好地区分AA和CA TN BCA？”从策略上讲，我们将使用由AA和CA TN BCA患者衍生的异种移植物产生的CYBRID系统来分析转移性BCA的线粒体特异性变化。 Kaipparettu实验室已经提供了来自不同TN乳腺AA和CA核背景的0个细胞。这样产生的cybrid将通过下一代测序确认其线粒体功能，核的确认，并使用体外和体内肿瘤形成/浸润测定法对表型变化进行了评估。此后，将针对AA和CA线粒体的Cybrid进行SRC途径的修饰。为了识别新的途径，将通过微阵列分析Cybrids的MRR，并将使用已建立的生物统计学和生物信息学管道（Oncomine Concept映射）与Biostatistical Cregighton博士一起检查基因表达，以与AA和Ca tnn Bca Metastass相关。将使用细胞系和异种移植模型评估提名的途径在TN BCA进程中的作用。总体而言，我们期望为AA和CA TN BCA进展发展开发的第一条线粒体驱动的致癌性特征。在临床上，我们希望将其翻译成AA TN BCA的新药物靶标。