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）：对于三阴性 BCa (TN BCa)，目前缺乏对驱动途径的了解，因此通常使用更通用的疗法进行治疗。目前尚无临床上接受的 TN BCa 治疗靶点和预测其转移潜力的靶点。虽然白种人 (CA) 女性的 BCa 发病率较高，但非洲裔美国 (AA) 女性因 BCa 导致的死亡较高。重要的是，AA 患者更有可能被诊断为三阴性 (TN) BCa，并且比 CA 处于更晚期。线粒体被认为是细胞的能量之家，与肿瘤的发生和进展密切相关，因此可以作为化疗的潜在靶点。随着跨线粒体细胞杂种（cybrid）技术的出现，现在可以在确定的核背景下检查肿瘤相关线粒体对肿瘤生长和发展的具体贡献。 Cybrids 是通过将含有目标线粒体的去核细胞与 ?0 受体细胞（含有被消融的线粒体 DNA 的细胞）融合而构建的。在体外和体内环境中使用这项技术，我们证明了 TN BCa 线粒体逆行调节 (MRR) 进展的关键作用。我们还确定了癌症线粒体对 Src 致癌途径翻译后修饰的关键调节。我们使用来自 AA 和 CA TN BCa 细胞系的线粒体杂种进行的初步分析表明，核基因的线粒体逆行调节 (MRR) 在 AA 和 CA 细胞中是不同的。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 博士在生成患者来源异种移植物方面的专业知识以及 Creighton 博士在生物信息学方面的专业知识相结合，以评估一个临床挑战性问题：“我们如何更好地区分 AA 和 CA TN BCa 的 MRR？”从策略上讲，我们将使用 AA 和 CA TN BCa 患者来源的异种移植物生成的 cybrid 系统来分析转移性 BCa 中线粒体特异性的改变。 Kaipparettu 实验室已提供来自不同 TN 乳腺来源 AA 和 CA 核背景的 ?0 细胞。由此产生的细胞杂种将通过下一代测序来确认其线粒体功能、核起源，并使用体外和体内肿瘤形成/侵袭测定来评估表型变化。此后，将分析具有 AA 和 CA 线粒体的细胞杂种的 Src 途径修饰。为了确定新的途径，将通过微阵列分析 cybrids 的 MRR，并使用已建立的生物统计学和生物信息学流程（Oncomine 概念图）与生物统计学家 Creighton 博士一起检查基因表达，以生成与 AA 和 AA 相关的致癌特征和途径。 CA TN BCa 转移。将使用细胞系和异种移植模型评估指定途径在 TN BCa 进展中的作用。总体而言，我们期望开发出首个线粒体驱动的 AA 和 CA TN BCa 进展的致癌特征。在临床上，我们期望这些成果能够转化为 AA TN BCa 的新药物靶点。