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：
8062885
负责人：
M. SAEED SHEIKH
金额：
$ 20.73万
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 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8062885
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 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）：乳腺癌在美国和全球范围内是一个主要的健康问题，因此，迫切需要识别和开发乳腺癌的新颖标志物，以促进早期诊断和对治疗的反应，并作为开发新型治疗方法的靶标。线粒体参与了各种细胞过程，包括控制凋亡，线粒体功能障碍也与乳腺癌有关。该应用建议在人乳腺癌中表征新型DNA损伤调节的线粒体抗凋亡蛋白CHCM1（盘绕的螺旋螺旋螺旋形态1）。我们的初步结果表明，人类乳腺癌中CHCM1的表达增加，其敲低使乳腺癌细胞对诱导抗癌药物诱导的凋亡敏感。我们的结果还表明，CHCM1与控制线粒体CRISTAE结构有关，并且它与线粒体蛋白质相互作用，这是另一种线粒体蛋白。我们的假设是CHCM1是一种新型的抗凋亡分子，在乳腺癌细胞存活和肿瘤发生中起着重要作用。我们还假设CHCM1可以成为乳腺癌的有价值的新颖标记，也可以作为开发较新的癌症治疗方法的分子靶标。我们的假设也是，CHCM1与丝线相互作用以控制线粒体Cristae的结构完整性并调节Cristae重塑。我们提出了三个特定的目的来检验这些假设。具体目的1是研究原发性乳腺癌样品中的CHCM1表达并与正常组织相匹配。具体目的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。特定目标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在乳腺癌发育和进展中的作用的宝贵信息，并促进CHCM1作为乳腺癌的新标记，以及较新的治疗方法的目标。该结果还将提供对线粒体CRISTAE结构调节的分子机制的宝贵见解，并重塑与乳腺癌病理生物学有关。公共卫生相关性：拟议研究的结果将提供有关CHCM1在乳腺癌发展和进展中的作用的宝贵信息，并促进CHCM1作为乳腺癌的新标记，并促进开发新的治疗方法。该结果还将提供对线粒体CRISTAE结构调节的分子机制的宝贵见解，并重塑与乳腺癌病理生物学有关。