ENERGY RESTRICTION AND MAMMARY CARCINOGENESIS

我们假设运动和卡路里限制抑制了 通过共同的机制致癌，对两者都至关重要的是 身体维持能量平衡(能量平衡)的方式 面对强加的能源限制状态(ERS)。因此，我们看到 将这些调查领域汇聚成一个研究重点。 在这项赠款申请中，我们建议研究ERS诱导的影响 通过运动和限制热量来1)探讨高血压的起源(S) 被归因于ERS的癌症抑制活性，以及2)决定是否 ERS只会导致癌症发生的数量减少或 具有特定基因改变的肿瘤是否选择性地 被禁止了。这些信息将为基因活动提供洞察力 在ERS中被特别改变，最终揭示了 保护机制。提出了四个具体目标。 目的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？假设 皮质类固醇水平升高是导致癌症的原因之一。 将评估由于能量限制而造成的抑制。蛋白质结合 血浆和尿液中的游离皮质类固醇将通过 放射免疫法和高效液相色谱法检测特定代谢物。 目的2.ERS是否简单地减少了癌症的发生 致病标记物还是发生在能量上的肿瘤受到限制 与不受限制的老鼠相比，代表了不同的致病种群 肿瘤：Ha-ras功能改变将使用PCR-RFLP进行评估 分析和/或免疫组织化学技术通过 视频图像分析。其他致病标志物将被研究为 他们在肿瘤模型中的参与得到了验证。 目的3.克隆扩增过程是否受到ERS的影响？如果是， 调节这一效应的因素：携带突变基因的细胞群体的扩张 HA-ras等位基因将通过聚合酶链式反应进行量化。克隆中的变化 将进一步研究扩展，以确定单元格是否发生变化 涉及细胞增殖或细胞死亡。 目的4.内质网刺激是否导致上皮或间充质改变 乳腺的组成部分，是组织的特征 重构，这可能在观察到的乳房抑制中发挥作用 致癌？ERS诱导血管内皮细胞外基质的变化 乳腺。利用Western和Northern杂交技术， 将确定这些变化的数量和质量性质 及其与内质网抑制乳腺癌发生的关系 调查过了。 ERS是一种非常有效、非侵入性、非药理学的方法。 预防许多器官的癌症，包括乳房，但 它的作用机制(S)尚不清楚。对其机理的认识(S) 可能会导致新的、广泛适用和易于容忍的方法 为主要人群提供癌症预防和控制服务。

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.