A novel biomarker and therapeutic target for breast cancer

乳腺癌的新型生物标志物和治疗靶点

基本信息

批准号：
8220835
负责人：
M. SAEED SHEIKH
金额：
$ 17.35万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8220835
关键词：
Affect Antineoplastic Agents Apoptosis Apoptotic Bioinformatics Biological Markers Breast Cancer Cell Cell Survival Cell physiology Coupled Crista ampullaris DNA Damage Data Development ERBB2 gene Early Diagnosis Future Growth Health Human Lesion Link Malignant Neoplasms Mammary Neoplasms Mitochondria Mitochondrial Crista Mitochondrial Proteins Molecular Molecular Profiling Molecular Target Morphology Mus Noninfiltrating Intraductal Carcinoma Normal tissue morphology Outcome Outcome Study Play Proteins Regulation Role Sampling Specimen Staging Structure Testing Therapeutic Xenograft Model base cohort in vivo insight mRNA Expression malignant breast neoplasm mitochondrial dysfunction novel novel marker novel therapeutic intervention outcome forecast pre-clinical public health relevance response small molecule therapeutic target tool triple-negative invasive breast carcinoma tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is a major health problem here in the US and globally and thus, there is an urgent need to identify and develop novel markers for breast cancer that would facilitate early diagnosis and response to therapy and also serve as targets to develop novel therapeutic approaches. Mitochondria are involved in various cellular processes including control of apoptosis and mitochondrial dysfunction has also been associated with breast cancer. This application proposes to characterize a novel DNA damage-regulated mitochondrial anti-apoptotic protein CHCM1 (Coiled coil Helix Cristae Morphology 1) in human breast cancer. Our preliminary results indicate that CHCM1 expression is increased in human breast cancers and its knockdown sensitizes breast cancer cells to apoptosis induced by DNA damage inducing anticancer drugs. Our results also indicate that CHCM1 is linked to controlling mitochondrial cristae structures and that it interacts with mitofilin, which is another mitochondrial protein. Our hypothesis is that CHCM1 is a novel anti-apoptotic molecule that plays an important role in breast cancer cell survival and tumorigenesis. We also hypothesize that CHCM1 can potentially serve as a valuable novel marker for breast cancer and a molecular target to develop newer cancer therapeutic approaches. It is also our hypothesis that CHCM1 interacts with mitofilin to control the structural integrity of mitochondrial cristae and regulate cristae remodeling. We are proposing three specific aims to test these hypotheses. Specific aim 1 is to investigate CHCM1 expression in primary breast cancer samples and matching normal tissues. Specific aim 2 is to investigate the role of CHCM1 in in vivo breast cancer growth using a mouse xenograft model. Specific aim 3 involves structural functional characterization of CHCM1. The outcome of the proposed studies, if successful, will provide valuable information about the role of CHCM1 in breast cancer development and progression and facilitate the development of CHCM1 as a novel marker for breast cancer and a target for newer therapeutic approaches. The outcome will also provide valuable insights into the molecular mechanisms involved in regulation of mitochondrial cristae structure and remodeling particularly as they relate to pathobiology of breast cancer. PUBLIC HEALTH RELEVANCE: The outcome of the proposed studies will provide valuable information about the role of CHCM1 in breast cancer development and progression and facilitate the development of CHCM1 as a novel marker for breast cancer and a target to develop newer therapeutic approaches. The outcome will also provide valuable insights into the molecular mechanisms involved in regulation of mitochondrial cristae structure and remodeling particularly as they relate to pathobiology of breast cancer.

描述（由申请人提供）：乳腺癌是美国和全球的一个主要健康问题，因此，迫切需要识别和开发新的乳腺癌标记物，以促进早期诊断和治疗反应，并作为目标是开发新的治疗方法。线粒体参与各种细胞过程，包括细胞凋亡的控制，线粒体功能障碍也与乳腺癌有关。本申请旨在表征人类乳腺癌中一种新型 DNA 损伤调节线粒体抗凋亡蛋白 CHCM1（卷曲螺旋螺旋形态 1）。我们的初步结果表明，CHCM1 表达在人类乳腺癌中增加，并且其敲低使乳腺癌细胞对诱导 DNA 损伤的抗癌药物诱导的细胞凋亡敏感。我们的结果还表明 CHCM1 与控制线粒体嵴结构有关，并且它与另一种线粒体蛋白 mitofilin 相互作用。我们的假设是CHCM1是一种新型抗凋亡分子，在乳腺癌细胞存活和肿瘤发生中发挥重要作用。我们还假设 CHCM1 有可能作为乳腺癌的一种有价值的新型标记物和开发新的癌症治疗方法的分子靶标。我们还假设 CHCM1 与 mitofilin 相互作用来控制线粒体嵴的结构完整性并调节嵴重塑。我们提出三个具体目标来检验这些假设。具体目标1是研究原发性乳腺癌样本和匹配的正常组织中CHCM1的表达。具体目标 2 是使用小鼠异种移植模型研究 CHCM1 在体内乳腺癌生长中的作用。具体目标 3 涉及 CHCM1 的结构功能表征。拟议研究的结果如果成功，将提供有关 CHCM1 在乳腺癌发生和进展中的作用的有价值的信息，并促进 CHCM1 作为乳腺癌新标志物和新治疗方法靶点的发展。该结果还将为参与线粒体嵴结构和重塑调节的分子机制提供有价值的见解，特别是与乳腺癌病理学相关的分子机制。公共卫生相关性：拟议研究的结果将提供有关 CHCM1 在乳腺癌发生和进展中的作用的有价值的信息，并促进 CHCM1 作为乳腺癌新标志物和开发新治疗方法的目标的发展。该结果还将为参与线粒体嵴结构和重塑调节的分子机制提供有价值的见解，特别是与乳腺癌病理学相关的分子机制。