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

描述（由申请人提供）：在过去的50年里，乳腺癌的发病率一直在上升，现在是美国妇女死亡的第二大原因。为了找出原因，人们正在研究环境暴露和饮食因素。NF - ?B家族转录因子在许多疾病中起着至关重要的作用，包括癌症、心血管疾病、肺病、肥胖和糖尿病。NF - ?在几乎所有的非B细胞中，B因子以无活性复合物的形式被隔离在细胞质中。令人惊讶的是，NF-？在典型致癌物7,12-二甲基苯(a)蒽（DMBA）诱导的大鼠乳腺肿瘤和95%以上的原发性人乳腺癌标本中均观察到B。抑制NF-？B诱导细胞凋亡或减缓生长，而MMTV-c-Rel转基因小鼠表明c-Rel可能在晚发性乳腺肿瘤发生中起因果作用。重要的是，发现突变的Ras和Her-2/neu过表达，可以由DMBA暴露诱导，激活NF- B。DMBA激活了多个NF-？小鼠乳腺肿瘤和c- rel驱动的乳腺癌细胞系中的B复合物。最近，PI的实验室发现了一种全新的RelB合成途径，表明RelB促进乳腺癌上皮细胞向间充质转化（EMT），表明在人类乳腺肿瘤和细胞系中诱导IKK5/i激酶在维持NF-？B的活性和转化，并暗示CK2参与IKK5/i的激活。在这一修订后的申请中，PI建议测试由环境致癌物介导的遗传和表观遗传改变汇聚诱导或增强多种NF-？B复合物，从而促进乳腺癌细胞更具侵袭性的表型。因此，抑制NF-？B将恢复恶性表型。癌症流行病学研究表明，绿茶摄入量与乳腺癌发病率呈负相关。绿茶含有丰富的抗氧化多酚（GTPs）；最丰富的是表没食子儿茶素-3没食子酸酯（EGCG）。EGCG抑制NF-？B通过Her- 2/neu信号。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驱动细胞的侵袭性表型，并减缓Her-2/新乳腺癌细胞系对曲妥珠单抗的增殖。在这个修订的新RO1申请中，提出了三个目标：(1)阐明NF-？B络合物促进转化；(2)阐明IKK5/i在乳腺癌发生中的功能作用及IKK5/i启动子激活的机制；(3)对gtp抑制Her-2/新肿瘤（包括曲妥珠单抗耐药肿瘤）生长的能力进行临床前动物试验。阳性结果可以很容易地转化为临床。关于个体NF-?的重要信息被环境致癌物或癌基因异常激活的促进浸润性乳腺癌的B复合物将会出现；研究结果应适用于涉及NF- B的广谱疾病。公共卫生相关性。本应用程序侧重于环境暴露在美国妇女乳腺癌发病率增加中的潜在作用，特别是核因子家族(NF-？B家族)已成为包括癌症在内的广泛疾病的治疗目标。致癌物诱导致癌基因的过度表达或突变，这些基因通过这一系列因素发出信号，PI的研究小组已经确定了导致它们表达的新途径，并表明绿茶成分可以逆转它们的激活，甚至在对常用疗法有抵抗力的细胞中也是如此。因此，将进行绿茶成分对抗抗体治疗的乳腺癌细胞的临床前测试，如果成功，这种方法可以很容易地转化为临床。

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.