Roles of NF-kB/Rel in the pathogenesis of breast cancer

NF-kB/Rel 在乳腺癌发病机制中的作用

• 批准号: 8059614
• 负责人: GAIL E. SONENSHEIN
• 金额: $ 33.76万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059614
• 关键词: Adverse effects; Affect; American; Anchorage-Independent Growth; Animal Testing; Anthracenes; Antibody Therapy; Antioxidants; Antiviral Agents; Apoptosis; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Binding; Biological Assay; Breast; Breast Cancer Cell; Cancer Etiology; Cancer cell line; Carcinogenesis Mechanism; Carcinogens; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cell Proliferation; Cell physiology; Cells; Clinic; Complement Factor B; Complex; Consumption; Cytoplasm; DNA Damage; Data; Development; Diabetes Mellitus; Dietary Factors; Disease; Disease Progression; Drug resistance; Environmental Carcinogens; Environmental Exposure; Epidemiologic Studies; Epigallocatechin Gallate; Epigenetic Process; Epithelial; Epithelial Cells; Exposure to; Factor V; Family; Gene Activation; Genes; Genetic; Green tea; Growth; Heavy Metals; Human; Immune response; Immunity; In Vitro; Incidence; Individual; Inflammatory Response; JUN gene; Lead; Lung diseases; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Mesenchymal; Microarray Analysis; Morbidity - disease rate; Mouse Mammary Tumor Virus; Mus; Mutation; NF-kappa B; Neoplastic Cell Transformation; Normal tissue morphology; Nuclear Family; Obesity; Oncogenes; Oxidative Stress; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; Phosphotransferases; Play; Pleural effusion disorder; Property; Rattus; Reporting; Resistance; Roche brand of trastuzumab; Rodent; Role; Signal Transduction; Signal Transduction Pathway; Specimen; Sprague-Dawley Rats; TNFRSF5 gene; Testing; Tissues; Transactivation; Transcription Factor AP-1; Transgenic Mice; Translating; Trastuzumab; Tumor Burden; Tumor Cell Line; Tumor-Derived; Virus Diseases; Woman; Xenograft Model; cigarette smoking; dimethylbenzanthracene; drinking; early onset; epithelial to mesenchymal transition; gallocatechol; in vivo; inhibitor/antagonist; mRNA Expression; malignant breast neoplasm; malignant phenotype; mouse model; mutant; neoplastic cell; overexpression; p65; polyphenol; pre-clinical; promoter; public health relevance; pulmonary function; research clinical testing; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Breast cancer incidence has been increasing over the past 50 years, and is now the second leading cause of death among American women. In an attempt to find the reasons, environmental exposure and dietary factors are being studied. The NF-?B family of transcription factors plays critical roles in many diseases, including cancer, cardiovascular, pulmonary disease, obesity and diabetes. NF-?B factors are sequestered in the cytoplasm in an inactive complex in almost all non-B cells. Surprisingly, aberrant activation of NF-?B was observed in rat mammary tumors induced by the prototypic carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) and over 95% of primary human breast cancer specimens. Inhibition of NF-?B induced apoptosis or slowed growth, while an MMTV-c-Rel transgenic mouse showed that c-Rel can play a causal role in late onset mammary tumorigenesis. Importantly, mutant Ras and Her-2/neu overexpression, which can be induced by DMBA exposure, were found to activate NF-?B. DMBA activated multiple NF-?B complexes in mouse mammary tumors and in a c-Rel-driven mammary cancer cell line. More recently, the PI's lab has identified a de novo RelB synthesis pathway, shown that RelB promotes epithelial to mesenchymal transition (EMT) of breast cancer, demonstrated that induction of the IKK5/i kinase in human breast tumors and cell lines plays an important role in maintenance of NF-?B activity and transformation, and implicated CK2 in IKK5/i activation. In this revised application, the PI proposes to test the central hypothesis that genetic and epigenetic alterations mediated by environmental carcinogens converge to induce or enhance the activity of multiple NF-?B complexes, thereby promoting a more invasive phenotype of breast cancer cells. Thus, inhibition of NF-?B will revert the malignant phenotype. Cancer epidemiological studies have shown an inverse association between green tea consumption and breast cancer incidence. Green tea is rich in polyphenols (GTPs) with anti-oxidant properties; the most abundant is epigallocatechin-3 gallate (EGCG). EGCG inhibits activation of NF-?B by Her- 2/neu signaling. Recently, green tea or EGCG was shown to reduce the invasive phenotype of DMBA-induced rat mammary tumors and Rel-driven cells in culture, and to slow proliferation of Her-2/neu breast cancer cell lines resistant to trastuzumab. In this revised new RO1 application, three aims are proposed: to (1) elucidate the roles of NF-?B complexes in promoting transformation; (2) elucidate the functional roles of IKK5/i in mammary carcinogenesis and the mechanism of IKK5/i promoter activation; (3) perform pre-clinical animal testing of the ability of GTPs to inhibit growth of Her-2/neu cancers, including those resistant to trastuzumab. Positive findings can readily be translated to the clinic. Important information on the roles of individual NF-?B complexes that are aberrantly activated by environmental carcinogens or oncogenes in promoting invasive breast cancer will be forthcoming; findings should be applicable to wide-spectrum of diseases involving NF-?B. PUBLIC HEALTH RELEVANCE. This application focuses on the potential role of environmental exposure in the increase in breast cancer incidence in American women, and specifically on a family of nuclear factors (NF-?B family) that have become a target for therapy in a wide spectrum of diseases, including cancer. Carcinogens induce overexpression or mutation in cancer-causing genes that signal via this family of factors, and the PI's group has identified new pathways leading to their expression and shown that green tea components can reverse their activation, even in cells resistant to commonly used therapies. Thus, pre-clinical testing of green tea components on breast cancer cells that are resistant to antibody therapy will be performed, and if successful, this approach can readily be translated to the clinic.

描述（由申请人提供）：过去 50 年来，乳腺癌发病率一直在上升，目前已成为美国女性第二大死因。为了找到原因，正在研究环境暴露和饮食因素。转录因子 NF-κB 家族在许多疾病中发挥着关键作用，包括癌症、心血管、肺部疾病、肥胖和糖尿病。在几乎所有非 B 细胞中，NF-κB 因子以非活性复合物的形式被隔离在细胞质中。令人惊讶的是，在原型致癌物 7,12-二甲基苯并（a）蒽（DMBA）诱导的大鼠乳腺肿瘤和超过 95% 的原发性人类乳腺癌样本中观察到 NF-κB 的异常激活。抑制 NF-κB 会诱导细胞凋亡或减缓生长，而 MMTV-c-Rel 转基因小鼠表明 c-Rel 在晚发性乳腺肿瘤发生中发挥因果作用。重要的是，突变体 Ras 和 Her-2/neu 过表达（可由 DMBA 暴露诱导）被发现可激活 NF-κB。 DMBA 在小鼠乳腺肿瘤和 c-Rel 驱动的乳腺癌细胞系中激活多个 NF-κB 复合物。最近，PI的实验室已经确定了从头RelB合成途径，表明RelB促进乳腺癌上皮间质转化（EMT），证明IKK5/i激酶在人类乳腺肿瘤和细胞系中的诱导在维持NF-κB活性和转化中发挥重要作用，并表明CK2参与IKK5/i激活。在此修订后的申请中，PI 提议测试中心假设，即由环境致癌物介导的遗传和表观遗传改变共同诱导或增强多种 NF-κB 复合物的活性，从而促进乳腺癌细胞更具侵袭性的表型。因此，抑制NF-κB将恢复恶性表型。癌症流行病学研究表明，绿茶摄入量与乳腺癌发病率呈负相关。绿茶富含具有抗氧化特性的多酚（GTP）；最丰富的是表没食子儿茶素-3没食子酸酯（EGCG）。 EGCG 通过 Her-2/neu 信号传导抑制 NF-κB 的激活。最近，绿茶或 EGCG 被证明可以减少 DMBA 诱导的大鼠乳腺肿瘤和培养中的 Rel 驱动细胞的侵袭表型，并减缓对曲妥珠单抗耐药的 Her-2/neu 乳腺癌细胞系的增殖。在这个修订后的新RO1申请中，提出了三个目标：（1）阐明NF-κB复合物在促进转化中的作用； （2）阐明IKK5/i在乳腺癌发生中的功能作用以及IKK5/i启动子激活的机制； (3) 对 GTP 抑制 Her-2/neu 癌症（包括对曲妥珠单抗耐药的癌症）生长的能力进行临床前动物测试。积极的发现可以很容易地转化为临床。关于被环境致癌物或癌基因异常激活的单个 NF-κB 复合物在促进浸润性乳腺癌中的作用的重要信息即将发布；研究结果应适用于涉及 NF-κB 的广谱疾病。公共卫生相关性。该应用重点关注环境暴露在美国女性乳腺癌发病率增加中的潜在作用，特别是核因子家族（NF-κB家族），这些因子已成为包括癌症在内的多种疾病的治疗靶标。致癌物会诱导致癌基因过度表达或突变，这些基因通过这一系列因子发出信号，PI的研究小组已经确定了导致其表达的新途径，并表明绿茶成分可以逆转其激活，即使在对常用疗法有抵抗力的细胞中也是如此。因此，将对绿茶成分对抗体治疗耐药的乳腺癌细胞进行临床前测试，如果成功，这种方法可以很容易地转化为临床。