Role of IRF-1 in Tumor Suppression of Breast Cancer

IRF-1 在乳腺癌肿瘤抑制中的作用

• 批准号: 7480271
• 负责人: JOHN H YIM
• 金额: $ 13.2万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480271
• 关键词: Adenoviruses; Animals; Apoptosis; Apoptosis Inhibitor; Apoptotic; Award; Basic Science; Bilateral; Biological; Breast; Breast Cancer Cell; Breast Cancer Treatment; CDKN1A gene; Cancer Etiology; Cancer Vaccines; Caspase; Cell Cycle; Cell Cycle Arrest; Cell Cycle Proteins; Cell Cycle Regulation; Cell Line; Cell Separation; Cells; Cessation of life; Cross Presentation; Data; Dendritic Cells; Discipline; Disease; Disease regression; Distal; Educational process of instructing; Engineering; Estrogen Antagonists; Estrogen Therapy; Genes; Goals; Growth; Human; Image; Immune; Immune response; Immunity; Immunocompetent; Immunohistochemistry; In Situ; In Vitro; Inbred C3H Mice; Infiltration; Injection of therapeutic agent; Interferon Regulatory Factor 1; Interferons; Lead; Lesion; Link; Malignant Neoplasms; Mediating; Mentors; Mentorship; Methods; Modeling; Mus; Non-Malignant; Nuclear; Nude Mice; Play; Prevention; Prevention therapy; Protein Overexpression; Recombinants; Recruitment Activity; Relative (related person); Research; Research Personnel; Resected; Retinoids; Role; Scientist; Site; Surgeon; T-Cell Depletion; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Training Programs; Transcriptional Regulation; Transfection; Tumor Antigens; Tumor Immunity; Tumor Suppression; Tumor Suppressor Proteins; United States; Universities; Up-Regulation; Virus; Woman; career; cell type; chemokine; cytokine; cytotoxic; gene therapy; immunogenicity; improved; in vivo; in vivo Model; malignant breast neoplasm; mouse model; mutant; neoplastic cell; novel; novel strategies; oncoprotein p21; programs; prophylactic; therapeutic vaccine; transcription factor; translational study; tumor; tumor immunology; uptake; vector

DESCRIPTION (provided by applicant): The applicant seeks to become an outstanding surgeon-scientist. This proposal describes a 5 year training program that will provide didactic teaching, acquisition of new methods, interactions with other scientists, career guidance, and supervised research to develop him into a superb investigator. He has performed high-quality research at the University of Pittsburgh under the mentorship of Timothy R. Billiar and Walter Storkus for the last three years. To develop his research career, he seeks more time commitment to basic research which would be made possible by the K08 award. The program will promote the command of two disciplines, apoptosis/cell cycle regulation and tumor immunology. Dr. Billiar is a recognized leader in apoptosis studies, and Dr. Storkus is a recognized leader in tumor immunology. The applicant's research has strong links to both. Research will focus on the role of IRF-1 in tumor suppression of breast cancer in vitro and in vivo. In preliminary research recombinant adenovirus for IRF-1 (Ad-IRF-1) has been constructed and confirmed to have functional expression in mouse and human breast cells. Ad-IRF-1 has been found to inhibit the growth of breast cancer cells, but not non-malignant breast cells, and tumor suppression of breast cancer has been found in vitro and in vivo. The antitumor effect seems to be mediated by apoptotic, cell cycle, and immune factors. Using Ad-IRF-1 and in vitro and in vivo models the role of IRF-1 in breast cancer specific growth inhibition and enhanced tumor immunogenicity will be evaluated. The specific aims include: 1) Determine the direct role of apoptosis and cell cycle effects in IRF-1 induced cancer-specific growth inhibition in vitro and in vivo, 2) Evaluate the enhanced immunogenicity of tumor cells infected with Ad-IRF-1 in prophylactic and therapeutic murine tumor models, and 3) Determine the role of IRF-1 induced apoptosis in the breast cancer immune response. This research combines the strengths of the mentors, and defines the antitumor mechanism of apoptosis and tumor immunogenicity and the interaction between them in breast Ca by IRF-1.

描述（由申请人提供）：申请人寻求成为一名杰出的外科医生科学家。该提案描述了一个为期5年的培训计划，将提供教学，新方法的获取，与其他科学家的互动，职业指导和监督研究，以发展他成为一个优秀的调查员。他在匹兹堡大学进行了高质量的研究，师从蒂莫西·R·戈恩（Timothy R.比利亚尔和沃尔特·斯托库斯在过去的三年里。为了发展他的研究事业，他寻求更多的时间投入基础研究，这将是可能的K 08奖。该计划将促进两个学科，细胞凋亡/细胞周期调控和肿瘤免疫学的命令。Billiar博士是细胞凋亡研究领域公认的领导者，Storkus博士是肿瘤免疫学领域公认的领导者。申请人的研究与两者都有很强的联系。研究将集中在IRF-1在体外和体内乳腺癌肿瘤抑制中的作用。在前期研究中，已构建了IRF-1重组腺病毒（Ad-IRF-1），并证实其在小鼠和人乳腺细胞中具有功能性表达。已发现Ad-IRF-1抑制乳腺癌细胞的生长，但不抑制非恶性乳腺细胞的生长，并且已在体外和体内发现乳腺癌的肿瘤抑制。抗肿瘤作用似乎是由细胞凋亡、细胞周期和免疫因子介导的。使用Ad-IRF-1和体外和体内模型，将评价IRF-1在乳腺癌特异性生长抑制和增强的肿瘤免疫原性中的作用。具体目标包括：1）确定细胞凋亡和细胞周期效应在体外和体内IRF-1诱导的癌症特异性生长抑制中的直接作用，2）评价在预防性和治疗性鼠肿瘤模型中用Ad-IRF-1感染的肿瘤细胞的增强的免疫原性，和3）确定IRF-1诱导的细胞凋亡在乳腺癌免疫应答中的作用。本研究结合导师的优势，通过IRF-1明确乳腺癌细胞凋亡和肿瘤免疫原性的抗肿瘤机制及其相互作用。

项目成果

Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells.

• DOI: 10.1016/j.canlet.2014.12.033
• 发表时间: 2015-03-28
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Wang Y;Han E;Xing Q;Yan J;Arrington A;Wang C;Tully D;Kowolik CM;Lu DM;Frankel PH;Zhai J;Wen W;Horne D;Yip MLR;Yim JH
• 通讯作者: Yim JH

IRF-1 transcriptionally upregulates PUMA, which mediates the mitochondrial apoptotic pathway in IRF-1-induced apoptosis in cancer cells.

• DOI: 10.1038/cdd.2009.156
• 发表时间: 2010-04
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Gao, J.;Senthil, M.;Ren, B.;Yan, J.;Xing, Q.;Yu, J.;Zhang, L.;Yim, J. H.
• 通讯作者: Yim, J. H.

Interferon Regulatory Factor 1 (IRF-1) induces p21(WAF1/CIP1) dependent cell cycle arrest and p21(WAF1/CIP1) independent modulation of survivin in cancer cells.

• DOI: 10.1016/j.canlet.2011.12.027
• 发表时间: 2012-06-01
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Armstrong, Michaele J.;Stang, Michael T.;Liu, Ye;Gao, Jinbo;Ren, Baoguo;Zuckerbraun, Brian S.;Mahidhara, Raja S.;Xing, Quanhua;Pizzoferrato, Eva;Yim, John H.
• 通讯作者: Yim, John H.

Identification of a natural compound by cell-based screening that enhances interferon regulatory factor-1 activity and causes tumor suppression.

• DOI: 10.1158/1535-7163.mct-11-0304
• 发表时间: 2011-10
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Gao J;Wang Y;Xing Q;Yan J;Senthil M;Akmal Y;Kowolik CM;Kang J;Lu DM;Zhao M;Lin Z;Cheng CH;Yip ML;Yim JH
• 通讯作者: Yim JH