TARGETING THE AP-1 TRANSCRIPTION FACTOR TO PREVENT METASTASIS FROM BREAST CANCER

靶向 AP-1 转录因子预防乳腺癌转移

• 批准号: 8117278
• 负责人: Qiang Shen
• 金额: $ 13.74万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117278
• 关键词: Adverse effects; Basic Science; Biomedical Research; Blood; Blood Vessels; Bone Marrow; Brain; Breast Cancer Cell; Cancer Biology; Cancer Patient; Cause of Death; Cell Adhesion; Cell Communication; Cell-Matrix Junction; Cells; Cellular biology; Cessation of life; Clinical; Clinical Sciences; Commit; Cytomegalovirus; Development; Disease; Disseminated Malignant Neoplasm; Distant Metastasis; E-Cadherin; Education; Elements; Endothelial Cells; Endothelium; Environment; Estrogen receptor negative; Estrogen receptor positive; Event; Fatty acid glycerol esters; Fostering; Foundations; Gene Expression; Genes; Goals; Growth; Human; Immune system; In Vitro; Intervention; Lead; Liver; Localized Malignant Neoplasm; Lung; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Mediator of activation protein; Medical; Medicine; Metastatic Lesion; Metastatic Neoplasm to the Lung; Metastatic to; Methylation; Molecular; Molecular Biology; Mus; Neoplasm Metastasis; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Nude Mice; Oncogenes; Organ; Patients; Phenotype; Physicians; Prevention; Prevention strategy; Process; Proteins; Publications; Quality of life; Reproductive system; Research; Research Training; Role; Scientist; Site; Solid; Survival Rate; System; Testing; Tissues; Training; Transcription Factor AP-1; Transgenic Mice; Tubular formation; Woman; Xenograft procedure; bone; cancer cell; cancer therapy; career; career development; cell motility; college; effective intervention; effective therapy; gastrointestinal system; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; metastatic process; migration; mouse model; overexpression; prevent; programs; promoter; public health relevance; transcription factor

DESCRIPTION (provided by applicant): The candidate of this application is a physician scientist who obtained medical and basic biomedical research education, and completed postdoctoral research training in cancer biology. In the past ten years, the candidate has been extensively trained in cellular, molecular, and cancer biology. Immediate career goal of the candidate is to establish an independent research program to study cancer metastasis. Long-term goal is to lead independent research programs to identify targets and develop effective strategies for the prevention and treatment of cancer, and cancer metastasis. The candidate chooses to study metastasis because it counts for 90% of cancer death, while the molecular mechanisms for metastasis development are largely unknown. The elucidation of these processes may lead to the discovery of targets for effective intervention and will benefit cancer patients. The candidate is committed to a research career in cancer biology. The candidate's training and expertise in basic and clinical sciences well fit in his commitment to find a cure for cancer. The key elements of the research career plan includes a solid postdoctoral research training, a productive publication record, an important research field in cancer biology, and Baylor College of Medicine as the supporting environment that will foster candidate's career development. Breast cancer is the 2nd most common cancer in Western women, and metastasis to other organs is the major cause of death from this disease. The 5-year survival rate is approximately 98% for localized cancer, but approximately 26% for patients with distant metastasis. To date, there are no effective therapies for the prevention and treatment of metastasis from breast cancer. It is therefore an absolute clinical necessity to identify new strategies to treat established metastasis and to block the development of new metastasis. Many genes or set of genes regulate cancer metastasis. Transcription factors control the expression of these genes critical for metastasis, and thus are potential targets for intervention. The AP-1 transcription factor has been shown to regulate metastasis-related genes in breast cancer, and overexpression of a major component of AP- 1, cJun, produces a highly invasive phenotype. The candidate will test the hypothesis that the AP-1 factor is required for developing metastasis by mediating metastatic cell invasion, promoting transendothelial migration, stimulating new blood vessel formation, and regulating critical genes involved in metastasis; and blockade of AP-1 will inhibit invasion and migration of metastatic cells, prevent development of new metastasis, and suppress the growth of existing metastasis. Our objective is to define the role of AP-1 in cancer metastasis and blockade of AP-1 is an effective strategy to prevent and treat metastasis. Specifically, the candidate will (1) determine whether AP-1 is required for invasion and metastasis using xenograft and transgenic mouse models; (2) investigate whether AP-1 promotes transendothelial migration, new blood vessel formation; and (3) define the molecular mechanisms how AP-1 regulates migration and invasion by mediating E-cadherin, a major AP-1-regulated gene involved in metastasis. The proposed studies will determine whether the AP-1 factor is a major regulator of metastasis and provide the foundation and rationale to develop agents capable of disrupting the metastatic process. PUBLIC HEALTH RELEVANCE: We hypothesized that the AP-1 factor is required for developing metastasis by mediating metastatic cell invasion, promoting transendothelial migration, stimulating new blood vessel formation, and regulating critical gene expression involved in metastasis. The proposed studies will determine whether the AP-1 factor is a major regulator of metastasis. Results from this project will provide the foundation and rationale to develop agents capable of disrupting the metastatic process.

描述（由申请人提供）：本申请的候选人是一名医学科学家，接受过医学和基础生物医学研究教育，并完成了癌症生物学的博士后研究培训。在过去的十年中，该候选人在细胞、分子和癌症生物学方面接受了广泛的培训。候选人的近期职业目标是建立一个独立的研究计划来研究癌症转移。长期目标是领导独立研究项目，以确定目标并制定预防和治疗癌症以及癌症转移的有效策略。该候选人选择研究转移，因为它占癌症死亡的 90%，而转移发展的分子机制在很大程度上尚不清楚。阐明这些过程可能会发现有效干预的目标，并使癌症患者受益。该候选人致力于癌症生物学的研究事业。该候选人在基础科学和临床科学方面的培训和专业知识非常适合他寻找癌症治疗方法的承诺。研究职业计划的关键要素包括扎实的博士后研究培训、富有成效的发表记录、癌症生物学的重要研究领域以及贝勒医学院作为促进候选人职业发展的支持环境。 乳腺癌是西方女性第二大常见癌症，转移到其他器官是该疾病死亡的主要原因。局部癌症的 5 年生存率约为 98%，但远处转移患者的 5 年生存率约为 26%。迄今为止，尚无有效的疗法来预防和治疗乳腺癌转移。因此，临床绝对有必要确定新的策略来治疗已发生的转移并阻止新转移的发展。许多基因或一组基因调节癌症转移。转录因子控制这些对转移至关重要的基因的表达，因此是潜在的干预目标。 AP-1 转录因子已被证明可以调节乳腺癌中的转移相关基因，并且 AP-1 主要成分 cJun 的过度表达会产生高度侵袭性的表型。候选人将测试以下假设：AP-1 因子通过介导转移细胞侵袭、促进跨内皮迁移、刺激新血管形成以及调节参与转移的关键基因来促进转移；阻断AP-1将抑制转移细胞的侵袭和迁移，防止新转移瘤的发展，并抑制现有转移瘤的生长。我们的目标是明确 AP-1 在癌症转移中的作用，阻断 AP-1 是预防和治疗转移的有效策略。具体来说，候选人将（1）使用异种移植和转基因小鼠模型确定AP-1是否是侵袭和转移所必需的； (2)考察AP-1是否促进跨内皮迁移、新血管形成； (3) 定义AP-1如何通过介导E-钙粘蛋白（一种参与转移的主要AP-1调节基因）来调节迁移和侵袭的分子机制。拟议的研究将确定 AP-1 因子是否是转移的主要调节因子，并为开发能够破坏转移过程的药物提供基础和原理。 公共健康相关性：我们假设 AP-1 因子通过介导转移细胞侵袭、促进跨内皮迁移、刺激新血管形成以及调节参与转移的关键基因表达来形成转移。拟议的研究将确定 AP-1 因子是否是转移的主要调节因子。该项目的结果将为开发能够破坏转移过程的药物提供基础和基本原理。