ENERGY RESTRICTION AND MAMMARY CARCINOGENESIS

能量限制与乳腺癌发生

• 批准号: 2007851
• 负责人: Henry J Thompson
• 金额: $ 20.81万
• 依托单位: AMC CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2007851
• 关键词: alleles; breast neoplasms; caloric dietary content; cancer prevention; cell cycle; cell death; chemical carcinogenesis; corticosteroids; disease /disorder model; exercise; extracellular matrix; high performance liquid chromatography; laboratory rat; mammary epithelium; methylnitrosourea; neoplasm /cancer genetics; nonhuman therapy evaluation; northern blottings; nutrition related tag; oncogenes; polymerase chain reaction; reducing diet; restriction fragment length polymorphism; tumor antigens; western blottings

We hypothesize that exercise and caloric restriction inhibit carcinogenesis by common mechanisms and that crucial to both is the manner in which the body maintains energy homeostasis (energy balance) in the face of an imposed energy restricted state (ERS). We thus see convergence of these areas of investigation into one focus of research. In this grant application we propose to study the effects of ERS induced by exercise and caloric restriction to 1) investigate the origin(s) of the cancer inhibitory activity attributed to ERS, and 2) determine if ERS causes only a quantitative reduction in the occurrence of cancers or whether tumors with specific genetic alterations are selectively inhibited. This information will provide insights to the gene activities that are specifically being altered in ERS, ultimately shedding light on the mechanism of protection. Four specific aims are proposed. AIM 1. Does increased adrenal cortical activity play a specific role in the inhibition of mammary carcinogenesis by ERS? The hypothesis that elevated levels of cortical steroids play a causal role in the cancer inhibition due to energy restriction will be evaluated. Protein bound and free corticosteroids will be determined in plasma and urine by radioimmunoassay and specific metabolites detected by HPLC. AIM 2. Does ERS result in simply fewer carcinomas with the same pathogenetic markers or do the tumors that occur in energy restricted versus unrestricted rats represent pathogenetically distinct populations of tumors: Altered function of Ha-ras will be assessed using PCR-RFLP analyses and/or immunohistochemical techniques with quantification via videoimage analyses. Other pathogenetic markers will be investigated as their involvement in the tumor model is validated. AIM 3. Is the process of clonal expansion affected by ERS and if so, what mediates this effect: Expansion of cell populations bearing mutant Ha-ras alleles will be quantified via PCR. Alterations in clonal expansion will be further studied to determine if changes in cell proliferation or cell death are involved. AIM 4. Does ERS induce changes in the epithelial or mesenchymal component of the mammary gland that are characteristic of tissue remodeling and that may play a role in the observed inhibition of mammary carcinogenesis? ERS induces changes in the extracellular matrix of the mammary gland. Using Western and Northern blot techniques, the quantitative and qualitative nature of these changes will be identified and their relationship to inhibition of mammary carcinogenesis by ERS investigated. ERS is a profoundly effective, noninvasive, nonpharmacological approach to prevention of cancer in many organs, including the breast, yet the mechanism(s) by which it acts is unknown. Knowledge of its mechanism(s) may lead to novel, widely applicable and well tolerated approaches to cancer prevention and control for a major segment of the population.

我们假设运动和热量限制抑制了 致癌作用的共同机制，这两个关键是 身体维持能量平衡的方式（能量平衡） 能源限制状态（ERS）。 我们由此看到， 将这些研究领域融合为一个研究重点。 在这项拨款申请中，我们建议研究ERS诱导的 通过锻炼和热量限制，1）调查 归因于ERS的癌症抑制活性，和2）确定是否 ERS仅导致癌症发生率的数量减少， 具有特定基因改变的肿瘤是否选择性地 压抑 这些信息将为基因活动提供见解 在ERS中被特别改变， 保护机制。 提出了四个具体目标。 AIM 1. 肾上腺皮质活动增加是否在 ERS对乳腺癌发生的抑制作用？ 的假设 皮质类固醇水平的升高在癌症中起着因果作用 将评估由于能量限制而引起的抑制。 蛋白结合 血浆和尿液中的游离皮质类固醇将通过 放射免疫分析和HPLC检测的特定代谢物。 AIM 2. ERS是否仅仅导致较少的癌症， 发病标志物或发生在能量受限的肿瘤 与不受限制的大鼠相比， 肿瘤：使用PCR-RFLP评估Ha-ras功能的改变 分析和/或免疫组织化学技术， 视频图像分析 将研究其他致病标志物， 证实了它们参与肿瘤模型。 AIM 3. 克隆扩张的过程是否受到ERS的影响，如果是， 介导这种效应的是什么：携带突变体的细胞群的扩增 将通过PCR定量Ha-ras等位基因。 无性系变异 将进一步研究扩增，以确定细胞中的变化 涉及增殖或细胞死亡。 AIM 4. ERS是否会引起上皮或间质的变化 乳腺的组成部分，是组织的特征 这可能在观察到的乳腺癌的抑制中起作用。 致癌作用？ ERS诱导细胞外基质的变化， 乳腺 使用Western和北方印迹技术， 将确定这些变化的数量和质量性质 及其与ERS抑制乳腺癌发生的关系 研究了 ERS是一种非常有效的非侵入性非药物治疗方法 预防包括乳腺癌在内的许多器官的癌症， 其作用机制尚不清楚。 了解其机制 可能导致新的，广泛适用的和良好耐受的方法， 癌症的预防和控制为一个主要的人口部分。