Animal Model for Local Inflammation-Induced Breast Cancer

局部炎症诱发乳腺癌的动物模型

• 批准号: 7500316
• 负责人: Harikrishna Nakshatri
• 金额: $ 7.58万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500316
• 关键词: Ablation; Adrenergic beta-Antagonists; Angiogenic Switch; Animal Model; Animals; Apoptosis; Apoptotic; Biological Availability; Breast Cancer Cell; Breast Cancer Model; CXCR4 gene; Carcinoma; Cardiovascular Diseases; Cell Death; Cell Line; Cells; Chemoprevention; Chemopreventive Agent; Chronic; Clinic; Clinical; Clinical Trials; Colony-Stimulating Factors; Development; Disease regression; Doxycycline; Drug Kinetics; Epidemiologic Studies; Epithelial Cells; Estrogen Receptor alpha; Exposure to; Female; Gene Expression; Genetic; Goals; Growth; Growth Factor; Herb; Heregulin; Hyperplasia; IL8 gene; Immune; Immune system; Implant; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin-1 alpha; Interleukin-6; Invasive; Laboratories; Lesion; Link; Lung; Macrophage Activation; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modality; Modeling; Mus; NF-kappa B; Neoplasm Metastasis; Nuclear; Nude Mice; Numbers; Oncogenes; Oral; Pattern; Personal Satisfaction; Phase I Clinical Trials; Play; Premalignant; Property; Rapid Access to Intervention Development; Resistance; Role; Series; Signal Pathway; Solid Neoplasm; Staging; TNFSF10 gene; Tanacetum parthenium; Taxane Compound; Testing; Therapeutic; Toxic effect; Toxicology; Transgenic Mice; Transgenic Model; Translations; Tumor Necrosis Factor Activation; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Urokinase; Water; Week; activating transcription factor; analog; angiogenesis; base; cancer cell; cyclooxygenase 2; cytokine; epithelial to mesenchymal transition; human TNF protein; improved; in vivo; inhibitor/antagonist; leukemia; macrophage; malignant breast neoplasm; neoplastic; neoplastic cell; parthenolide; pre-clinical; prevent; programs; response; taxane; theories; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): The theory that tumors originate from regions of chronic inflammation has recently received support from considerable evidence obtained from a series of animal and epidemiological studies. It is now apparent that there is an interplay between epithelial cells and inflammatory cells, particularly macrophages, which is critical for progression of breast cancer. The key player that links inflammation to cancer is the transcription factor NF-?B, which regulates the expression of genes involved in proliferation, anti-apoptosis, invasion and metastasis. Constitutive activation of NF-?B in breast cancer has been well established by us and others. We have identified a number of signaling pathways that cause constitutive NF-?B activation in cancer cells including the action of cancer cell-derived IL-1a and heregulin. Our studies have shown that mammary tumor cell line derived from transgenic mice expressing her2/neu oncogene have markedly increased NF-?B activation and proliferation upon exposure to tumor necrosis factor (TNF). The latter is a major factor secreted by tumor associated macrophages and in so doing links inflammation to cancer. Recent studies have shown that inhibition of NF-?B in cancer cells using genetic approaches leads to conversion from TNF-induced proliferation to TRAIL-induced cancer cell death. Thus, inhibitors of NF-?B are ideal for preventing progression of pre-neoplastic lesions to cancer. As genetic ablation of NF-?B in cancer cells is not clinically possible, we have developed a water-soluble compound LC-1 with potent anti-NF-?B activity. The NCI's RAID program has confirmed that this agent has a favorable pharmacokinetic profile for clinical development and as such the compound will be tested in a phase I clinical trial for leukemia in 2007. The goal of this proposal is to define the chemopreventive potential of this compound in two animal models of breast cancer. We will test the hypothesis that by inhibiting NF-?B activity in pre-neoplastic lesions, LC-1 converts inflammation-induced tumor growth to inflammation-induced tumor regression through TRAIL. We also hypothesize that LC-1 will be particularly effective on inflammatory breast cancers, a rare but deadly form of breast cancer that is critically dependent on NF-?B for growth and survival. Two aims will test these hypotheses. Aim 1 will be to determine the effect of LC-1 on mammary tumor incidence, multiplicity and its effect on the angiogenic switch in the inducible MMTV-neu model of breast cancer. The second aim will be to define the ability of LC-1 to reduce growth and angiogenesis in an inflammatory model of breast cancer. For aim I, we will use the recently developed inducible transgenic model of breast cancer where activated neu is induced by treating 6.5 week old females with doxycycline. The resultant mammary tumors in these mice show a specific pattern of progression with hyperplasia followed by the angiogenic switch and then development of invasive carcinoma followed by lung metastasis. This model will allow us to test the effect of LC-1 on each of these stages and to evaluate the effect of LC-1 on the levels of different immune modulatory cells in the tumor microenvironment during different stages of breast cancer. For the inflammatory breast cancer model, we will use SUM149 cells implanted in nude mice as these cells are extremely sensitive to LC-1 mediated cell death. This study has the potential for translation to clinic because LC-1 has a favorable pharmacokinetic profile with no major toxicity in the preclinical toxicology studies. We propose that we will not completely eliminate but control NF-?B activity (similar to the approach with beta-blockers for cardiovascular diseases) so that normal activity of immune system is not compromised with LC-1 treatment.

描述（由申请人提供）： 肿瘤起源于慢性炎症区域的理论最近得到了来自一系列动物和流行病学研究的大量证据的支持。现在很明显，上皮细胞和炎症细胞，特别是巨噬细胞之间存在相互作用，这对乳腺癌的进展至关重要。将炎症与癌症联系起来的关键因素是转录因子NF-？B，其调节参与增殖、抗凋亡、侵袭和转移的基因的表达。NF-？B在乳腺癌中已经被我们和其他人很好地建立。我们已经确定了一些信号通路，导致组成性NF-？癌细胞中的B活化，包括癌细胞衍生的IL-1 a和调蛋白的作用。我们的研究表明，乳腺癌细胞系来源于转基因小鼠表达her 2/neu癌基因显着增加NF-？B在暴露于肿瘤坏死因子（TNF）后活化和增殖。后者是肿瘤相关巨噬细胞分泌的主要因子，因此将炎症与癌症联系起来。最近的研究表明，抑制NF-？使用遗传方法的癌细胞中的B导致从TNF诱导的增殖转化为TRAIL诱导的癌细胞死亡。因此，NF-？B是预防肿瘤前病变进展为癌症的理想选择。作为基因消融NF-？B在癌细胞是不可能的临床上，我们已经开发了一种水溶性化合物LC-1与有效的抗NF-？B活性。NCI的RAID计划已证实该药物具有良好的药代动力学特征，适合临床开发，因此该化合物将于2007年在白血病I期临床试验中进行测试。该提案的目标是确定该化合物在两种乳腺癌动物模型中的化学预防潜力。我们将测试的假设，通过抑制NF-？肿瘤前病变中的B活性，LC-1通过TRAIL将炎症诱导的肿瘤生长转化为炎症诱导的肿瘤消退。我们还假设，LC-1将是特别有效的炎性乳腺癌，一种罕见的，但致命的形式的乳腺癌，是严重依赖于NF-？B代表生长和存活。两个目标将检验这些假设。目的1将确定LC-1对乳腺肿瘤发病率、多样性的影响及其对乳腺癌的诱导型MMTV-neu模型中血管生成开关的影响。第二个目标是确定LC-1在乳腺癌炎症模型中减少生长和血管生成的能力。对于目标I，我们将使用最近开发的乳腺癌的诱导型转基因模型，其中通过用多西环素治疗6.5周龄的雌性来诱导活化的neu。在这些小鼠中产生的乳腺肿瘤显示出特定的进展模式，即增生，随后是血管生成转换，然后发展为浸润性癌，随后是肺转移。该模型将使我们能够测试LC-1对每个阶段的影响，并评估LC-1对乳腺癌不同阶段肿瘤微环境中不同免疫调节细胞水平的影响。对于炎性乳腺癌模型，我们将使用植入裸鼠中的SUM 149细胞，因为这些细胞对LC-1介导的细胞死亡极其敏感。该研究具有转化为临床的潜力，因为LC-1具有良好的药代动力学特征，在临床前毒理学研究中没有重大毒性。我们建议，我们不会完全消除，但控制NF-？B活性（类似于β-受体阻滞剂用于心血管疾病的方法），使得免疫系统的正常活性不受LC-1治疗的损害。