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

描述(申请人提供)：本申请的候选人是一名内科科学家，受过医学和生物医学基础研究教育，并完成了癌症生物学的博士后研究培训。在过去的十年里，这位候选人在细胞、分子和癌症生物学方面接受了广泛的培训。应聘者的直接职业目标是建立一个独立的研究项目来研究癌症转移。长期目标是领导独立的研究项目，以确定目标并开发有效的策略来预防和治疗癌症以及癌症转移。候选人选择研究转移是因为它占癌症死亡的90%，而转移发生的分子机制在很大程度上是未知的。阐明这些过程可能会导致发现有效干预的靶点，并将使癌症患者受益。这位候选人致力于癌症生物学的研究生涯。这位候选人在基础和临床科学方面的培训和专业知识与他寻找癌症治愈方法的承诺非常吻合。研究职业生涯计划的关键要素包括扎实的博士后研究培训、富有成效的出版记录、癌症生物学的重要研究领域，以及贝勒医学院作为支持候选人职业发展的环境。 乳腺癌是西方女性第二常见的癌症，转移到其他器官是这种疾病的主要死亡原因。局部癌症的5年生存率约为98%，而远处转移患者的5年生存率约为26%。到目前为止，还没有有效的治疗方法来预防和治疗乳腺癌转移。因此，找出治疗已有转移和阻止新转移发展的新策略在临床上是绝对必要的。许多基因或一组基因调节癌症的转移。转录因子控制着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转录因子被证明在乳腺癌中调节转移相关基因，AP-1的主要成分cJun的过度表达会产生高度侵袭性的表型。候选人将检验这一假设，即AP-1因子通过介导转移细胞侵袭、促进跨内皮细胞迁移、刺激新血管形成和调节参与转移的关键基因而在发生转移中是必需的；并且阻断AP-1将抑制转移细胞的侵袭和迁移，防止新转移的发展，并抑制现有转移的生长。我们的目的是明确AP-1在肿瘤转移中的作用，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)利用异种移植和转基因小鼠模型确定AP-1是否在侵袭和转移中是必需的；(2)研究AP-1是否促进跨内皮细胞迁移和新血管的形成；以及(3)确定AP-1如何通过介导E-钙粘蛋白来调节迁移和侵袭的分子机制，E-钙粘蛋白是AP-1调节的参与转移的主要基因。拟议的研究将确定AP-1因子是否是转移的主要调节因子，并为开发能够干扰转移过程的药物提供基础和理论基础。 公共卫生相关性：我们假设AP-1因子通过介导转移细胞侵袭、促进跨内皮细胞迁移、刺激新血管形成和调节与转移相关的关键基因表达而在发生转移中是必需的。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理论基础。

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.