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

描述（由申请人提供）：本申请的候选人是获得医学和基础生物医学研究教育的医师科学家，并完成了癌症生物学博士后研究培训。在过去的十年里，该候选人接受了细胞、分子和癌症生物学方面的广泛培训。候选人的近期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计划，以确定目标，并制定有效的策略，预防和治疗癌症，癌症转移。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是未知的。这些过程的阐明可能导致发现有效干预的靶点，并将使癌症患者受益。候选人致力于癌症生物学的研究事业。候选人在基础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促进候选人职业发展的支持环境。 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死亡的主要原因。局限性癌症的5年生存率约为98%，而远处转移患者的5年生存率约为26%。迄今为止，没有有效的治疗方法用于预防和治疗乳腺癌转移。因此，确定新的策略来治疗已建立的转移并阻断新转移的发展是绝对临床必要的。许多基因或基因组调节癌症转移。转录因子控制这些对转移至关重要的基因的表达，因此是干预的潜在靶点。AP-1转录因子已被证明可调节乳腺癌中的转移相关基因，AP- 1的主要成分cJun的过表达可产生高度侵袭性表型。候选人将检验以下假设：AP-1因子通过介导转移性细胞侵袭、促进跨内皮迁移、刺激新血管形成和调节参与转移的关键基因而为发展转移所必需; AP-1的阻断将抑制转移性细胞的侵袭和迁移，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。具体而言，候选人将（1）使用异种移植物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）研究AP-1是否促进跨内皮迁移，新血管形成;和（3）定义AP-1如何通过介导E-cadherin调节迁移和侵袭的分子机制，E-cadherin是参与转移的主要AP-1调节基因。拟议的研究将确定AP-1因子是否是转移的主要调节因子，并为开发能够破坏转移过程的药物提供基础和理论依据。 公共卫生相关性：我们假设AP-1因子是通过介导转移细胞侵袭、促进跨内皮迁移、刺激新血管形成和调节参与转移的关键基因表达来发展转移所必需的。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依据。

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.