A novel biomarker and therapeutic target for 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，迫切需要鉴定和开发新的乳腺癌标志物，以促进早期诊断和对治疗的反应，并作为开发新治疗方法的靶点。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。本申请提出表征人乳腺癌中的新型DNA损伤调节的线粒体抗凋亡蛋白CHCM 1（卷曲螺旋阻碍嵴形态学1）。我们的初步结果表明，CHCM 1表达增加，在人类乳腺癌和它的敲低敏感的乳腺癌细胞诱导的DNA损伤诱导抗癌药物诱导的凋亡。我们的研究结果还表明，CHCM 1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，CHCM 1是一种新的抗凋亡分子，在乳腺癌细胞的生存和肿瘤发生中起着重要作用。我们还假设CHCM 1可能作为乳腺癌的一个有价值的新标志物和开发新的癌症治疗方法的分子靶点。这也是我们的假设，CHCM 1与丝裂素相互作用，以控制线粒体嵴的结构完整性和调节嵴重塑。我们提出了三个具体目标来检验这些假设。具体目标1是研究CHCM 1在原发性乳腺癌样品和匹配的正常组织中的表达。具体目标2是使用小鼠异种移植模型研究CHCM 1在体内乳腺癌生长中的作用。具体目标3涉及CHCM 1的结构功能表征。如果成功，拟议研究的结果将提供有关CHCM 1在乳腺癌发展和进展中的作用的有价值的信息，并促进CHCM 1作为乳腺癌的新标志物和新治疗方法的靶点的发展。该结果还将提供有价值的见解，涉及线粒体嵴结构的调节和重塑的分子机制，特别是因为它们涉及到乳腺癌的病理生物学。 公共卫生相关性：拟议研究的结果将提供有关CHCM 1在乳腺癌发展和进展中的作用的有价值的信息，并促进CHCM 1作为乳腺癌新标志物和开发新治疗方法的靶点的发展。该结果还将提供有价值的见解，涉及线粒体嵴结构的调节和重塑的分子机制，特别是因为它们涉及到乳腺癌的病理生物学。

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.