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: 7596203
• 负责人: GAIL E. SONENSHEIN
• 金额: $ 33.72万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596203
• 关键词: Adverse effects; Affect; American; Anchorage-Independent Growth; Animal Testing; Anthracenes; Antibody Therapy; Antioxidants; Antiviral Agents; Apoptosis; Aromatic Polycyclic Hydrocarbons; B-Lymphocytes; 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; 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; IKK-i kinase; Immune; 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; Normal tissue morphology; Nuclear Family; Obesity; Oncogenes; Oxidative Stress; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; 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; mammary tumor virus; mouse model; mutant; neoplastic; neoplastic cell; overexpression; p65; polyphenol; pre-clinical; promoter; 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）：在过去的50年中，乳腺癌发病率一直在增加，现在是美国妇女中第二大死亡原因。为了找到原因，正在研究环境暴露和饮食因素。 NF-？B家族的转录因子在许多疾病中起着关键作用，包括癌症，心血管，肺部疾病，肥胖和糖尿病。 NF-？B因子在几乎所有非B细胞的非活性复合物中的细胞质中被隔离。出乎意料的是，原型致癌物7,12-二甲基苯子（A）蒽（DMBA）和超过95％的原发性人类乳腺癌标本诱导的大鼠乳腺肿瘤中观察到了NF-？B的异常激活。 NF-？B诱导的细胞凋亡或生长缓慢，而MMTV-C-REL转基因小鼠的抑制作用表明C- REL可以在晚期乳腺肿瘤发生中起因果作用。重要的是，发现可以通过DMBA暴露诱导的突变体RAS和HER​​-2/NEU过表达可激活NF-。 DMBA激活了小鼠乳腺肿瘤和C-REL驱动的乳腺癌细胞系中的多个NF- b络合物。最近，PI的实验室已经确定了从头恢复的合成途径，该途径表明，RERB促进了乳腺癌的间质转变（EMT）上皮，这表明，在人类乳腺肿瘤中诱导IKK5/I激酶在维持NF-？B活性和转化Ck5的IKK5/I激酶在维持Nf- b？b的活性和转化中起着重要作用。在此修订后的应用中，PI提议检验以环境致癌物介导的遗传和表观遗传改变的中心假设，以融合诱导或增强多个NF- b络合物的活性，从而促进乳腺癌细胞的更具侵入性的表型。因此，抑制NF-？b将恢复恶性表型。癌症流行病学研究表明，绿茶消耗与乳腺癌发病率之间存在逆关联。绿茶富含多酚（GTP），具有抗氧化特性。最丰富的是Epigallocatechin-3 Gallate（EGCG）。 EGCG通过HER-2/neu信号抑制NF-？B的激活。最近，绿茶或EGCG被证明可以减少培养中DMBA诱导的大鼠乳腺肿瘤和相关细胞的侵入性表型，并减慢HER-2/NEU乳腺癌细胞系对曲妥珠单抗的抗性。在此修订后的新RO1应用中，提出了三个目标：（1）阐明NF- b络合物在促进转型中的作用； （2）阐明IKK5/I在乳腺癌发生和IKK5/I启动子激活的机理中的功能作用； （3）对GTP抑制HER-2/NEU癌的生长的能力进行临床前动物测试，包括对曲妥珠单抗的耐药性。积极的发现很容易被转化为诊所。有关环境致癌物或癌基因在促进侵袭性乳腺癌中异常激活的单个NF- b络合物的作用的重要信息；调查结果应适用于涉及NF-的广泛疾病。公共卫生相关性。该应用的重点是环境暴露在美国女性乳腺癌发病率增加中的潜在作用，尤其是核因素（NF-？b家族）已成为包括癌症在内的各种疾病中的治疗的靶标。致癌物诱导通过该因子家族发出信号的引起癌症的基因的过表达或突变，并且PI组鉴定出了导致其表达的新途径，并表明绿茶成分也可以逆转其激活，即使在对常用疗法的细胞中也可以逆转其激活。因此，将进行抗抗体治疗的乳腺癌细胞上绿茶成分的临床前测试，如果成功，则可以轻松地将这种方法转化为诊所。