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Molecular characterization of endometrial cancer

子宫内膜癌的分子特征

基本信息

批准号：
8763450
负责人：
Christina Annunziata
金额：
$ 20.71万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8763450
关键词：
Accounting Address Adhesions African American Biochemical Biological Assay Cancer cell line Carcinoma Carcinoma in Situ Caucasians Caucasoid Race Cell Line Cells Cessation of life Characteristics Clear Cell Clinical Clinical Trials Design Collaborations Data Defect Dependence Diagnostic Disease Progression Distal Down-Regulation E-Cadherin Endometrial Endometrial Carcinoma Endometrial Hyperplasia Epithelial Epithelium Equilibrium Estrogens Event Family Future Gene Expression Gene Proteins Genetic Goals Histocompatibility Testing Histologic Histology In Vitro Inherited Location Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Mediating Molecular Molecular Abnormality Molecular Profiling Mutation NF-kappa B Nature Outcome Outcome Study Ovarian PTEN gene Papillary Pathway interactions Patients Production Publishing Recording of previous events Sampling Serous Signal Transduction Site Testing Therapeutic Tissue Microarray Uterine Cancer Uterine Polyp Variant Western Blotting Woman cytokine design improved inhibitor/antagonist mutant protein expression research study small molecule tumor

项目摘要

Preliminary data established the requirement for NF-kB signaling in a subset of endometrial cancer cell lines. In collaboration with G.L.Maxwell, we examined a signature of NF-kB activity in the gene expression profiles of endometrial cancers balanced for serous vs endometrioid histology and also distributed equally among African American (AA) and caucasian (C) women. We found that the signature was significantly higher in cancers from AA women, especially those of the serous histology variant. Ongoing projects in our lab, and in collaboration with the Maxwell lab, will continue to address the stated goals. We tested 9 endometrial cancer cell lines for their dependence on NF-kB signaling by treating them with IKKb small molecule inhibitor and quantifying viability in XTT assays. We plan to extend these experiments to additional cell lines, and in additional function assays such as adhesion, invasion and cytokine production. We identified at least 2 endometrial cancer cell lines that are sensitive to IKKb inhibition in vitro. We profiled gene expression changes in these 2 cell lines upon blockade of IKKb signaling using both a small molecule inhibitor and introduction of a mutant form of IkBa that serves as a "super-repressor" of IKKb-mediated signaling. We will confirm decrease in protein expression of the endometrial cancer-specific NF-kB targets by Western blot. These gene and protein signatures will allow us to specifically interrogate the endometrial cancer samples using gene expression profiles and tissue microarrays that are currently being collected and generated by our collaborator. The overall outcome of these studies will be to design clinical trials with NF-kB targeted agents for women whose endometrial cancers show evidence of pathway activation.

初步数据确定了子宫内膜癌细胞系亚群对NF-kB信号的需求。在与G.L.Maxwell的合作中，我们检测了NF-kB活性在子宫内膜癌的基因表达谱中的特征，这些基因表达谱在浆液和子宫内膜样组织学上是平衡的，并且在非洲裔美国人（AA）和高加索人(C)女性中也是均匀分布的。我们发现，AA女性的癌症中，尤其是浆液组织学变异的癌症中，这种特征明显更高。我们实验室正在进行的项目，以及与麦克斯韦实验室的合作，将继续解决既定的目标。我们用IKKb小分子抑制剂处理9个子宫内膜癌细胞系，并通过XTT测定它们对NF-kB信号的依赖性。我们计划将这些实验扩展到其他细胞系，并进行额外的功能分析，如粘附、侵袭和细胞因子产生。我们在体外鉴定了至少2种对IKKb抑制敏感的子宫内膜癌细胞系。我们使用小分子抑制剂和引入IkBa突变体作为IKKb介导信号的“超级抑制因子”阻断IKKb信号后，分析了这两种细胞系的基因表达变化。我们将通过Western blot证实子宫内膜癌特异性NF-kB靶点蛋白表达的降低。这些基因和蛋白质的特征将使我们能够使用基因表达谱和组织微阵列来特异性地询问子宫内膜癌样本，这些样本目前正在由我们的合作者收集和生成。这些研究的总体结果将是设计针对子宫内膜癌显示通路激活证据的妇女的NF-kB靶向药物的临床试验。