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从一系列动物和流行病学研究获得的大量证据的支持。现在显然，上皮细胞和炎性细胞，尤其是巨噬细胞之间存在相互作用，这对于乳腺癌的进展至关重要。将炎症与癌症联系起来的关键参与者是转录因子NF-？b，它调节与增殖，抗凋亡，侵袭和转移有关的基因表达。 NF-？B在乳腺癌中的构成激活已得到美国和其他人的良好确定。我们已经确定了许多引起癌细胞中组成型NF- b激活的信号传导途径，包括癌细胞衍生的IL-1A和此处调节蛋白的作用。我们的研究表明，源自表达HER2/NEU癌基因的转基因小鼠的乳腺肿瘤细胞系显着增加了NF-？B激活和暴露于肿瘤坏死因子（TNF）后的增殖。后者是与肿瘤相关的巨噬细胞分泌的主要因素，因此与癌症联系起来。最近的研究表明，使用遗传方法对癌细胞中NF-？B的抑制会导致TNF诱导的增殖转变为越野诱导的癌细胞死亡。因此，NF-？B的抑制剂是预防癌症前病变进展的理想选择。由于癌细胞中NF- b的遗传消融是不可能的，因此我们开发了具有有效抗NF-活性的水溶性化合物LC-1。 NCI的RAID计划已确认该药物具有有利的临床发育药代动力学特征，因此该化合物将在2007年的I期临床试验中进行测试。该提案的目的是定义两种化合物在两种乳腺癌动物模型中的化学预防潜力。我们将检验以下假设：通过抑制肿瘤前病变中的NF-？B活性，LC-1将炎症诱导的肿瘤生长转化为炎症诱导的肿瘤通过TARL的回归。我们还假设LC-1对炎症性乳腺癌特别有效，炎症性乳腺癌是一种罕见但致命的乳腺癌形式，严重依赖于NF-？B的生长和生存。两个目标将检验这些假设。 AIM 1将是确定LC-1对乳腺癌诱导型MMTV-NEU模型中乳腺肿瘤发生率，多样性及其对血管生成转换的影响。第二个目的是定义LC-1在乳腺癌炎症模型中降低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转基因模型，而活化的NEU是通过使用强力霉素治疗6.5周的女性来诱导的。这些小鼠中所得的乳腺肿瘤显示出具有增生的特定进展模式，然后是血管生成开关，然后发育的浸润性癌，然后是肺转移。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。对于炎症性乳腺癌模型，我们将使用植入裸鼠的SUM149细胞，因为这些细胞对LC-1介导的细胞死亡极为敏感。这项研究具有转化为诊所的潜力，因为LC-1具有有利的药代动力学特征，在临床前毒理学研究中没有主要毒性。我们建议我们不会完全消除，但是控制NF-？B活性（类似于用于心血管疾病的β受体阻滞剂的方法），以便通过LC-1治疗不会损害免疫系统的正常活性。