P53-dependent responses to toxicants in parous and nulliparous breast

经产和未产乳房对毒物的 P53 依赖性反应

• 批准号: 7289413
• 负责人: D. Joseph Jerry
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-07 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289413
• 关键词: Affect; Age; Animals; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Attention; Biological; Biological Markers; Breast; Cell Line; Chlorinated Hydrocarbons; Class; DNA Damage; Data; Endocrine; Environmental Carcinogens; Environmental Exposure; Evaluation; Experimental Models; Exposure to; Future; Gene Expression; Genotype; Human; Ionizing radiation; Lead; Literature; Mammary Gland Parenchyma; Mammary Neoplasms; Mediating; Molecular Profiling; Mus; Pathway interactions; Phenotype; Predisposition; Research Personnel; Sampling; Signal Transduction; TP53 gene; Tissues; Toxicology; Woman; carcinogenesis; comparative; environmental carcinogenesis; human study; malignant breast neoplasm; mouse model; parity; protective effect; response; toxicant

DESCRIPTION (provided by applicant): Associations between breast cancer and exposure to environmental carcinogens are often weak or inconsistent in the epidemiologic literature, even when strong experimental data exists. The strongest support for environmental carcinogenesis comes from mouse models showing that exposures such as ionizing radiation (IR) and polycyclic aromatic hydrocarbons (PAHs) increase mammary tumor formation. These same experimental models have shown that parity has a p53-mediated, protective effect against carcinogenesis. This application proposes a comparative toxicology approach for dissecting the biological pathways that lead to environmental carcinogenesis of the breast, with emphasis on interactions between environmental carcinogens, the p53 pathway, and parity. Three classes of environmental exposure, each with a strong epidemiologic and toxicological literature, have been selected for study: IR, PAHs, and organochlorines (OCs). The first two classes (IR and PAHs) both cause DNA damage and induce p53-dependent DNA damage responses, but the DNA damage mechanisms are different. In contrast, OCs do not act by directly damaging DNA, and thus, provide a negative control for p53-dependent signaling. OCs also provide a comparison for the PAHs as both PAHs and OCs can activate the aryl hydrocarbon receptor (AhR) and perturb endocrine action in the breast. In Aim 1, we will assess the p53 dependent effects of each toxicant using isogenic human breast cell lines (with and without expression of p53RNAi to knockdown p53 expression) and nulliparous Trp53+/+ and Trp53-/- mice. In Aim 2, we will examine gene expression profiles associated with parity in humans (using reduction mammoplasty samples) and mice, with specific attention to identifying p53-regulated gene expression. In Aim 3, the interaction between parity and environmental carcinogenesis will be assessed by comparing transcriptional responses to toxicants in parous and age-matched nulliparous mice. Differential responses to toxicants will be verified in explant cultures of human breast tissue from nulliparous and parous women (excess tissue from reduction mammoplasty). Thus, each aim will integrate human and mouse responses to define responses to toxicants and parity. The data from all three aims will be integrated to allow a complete, multifactorial evaluation of how environmental exposures to these toxicants, p53 signaling, and parity status interact to affect breast signaling, and ultimately carcinogenesis. These studies will define the mechanisms of environmentally-induced breast cancer, anchored on genotype-phenotype correlations that define susceptibility, and will identify new candidate biomarkers of susceptibility that can be used in future animal and human studies.

描述（由申请人提供）： 乳腺癌与暴露于环境致癌物之间的关联在流行病学文献中也通常很弱或不一致，即使存在强大的实验数据。对环境癌变的最强烈支持来自小鼠模型，表明诸如电离辐射（IR）和多环芳族烃（PAHS）等暴露会增加乳腺肿瘤的形成。这些相同的实验模型表明，平等性具有p53介导的针对致癌作用的保护作用。该应用提出了一种比较毒理学方法，用于剖析导致乳房环境致癌的生物学途径，重点是环境致癌物，p53途径和奇偶校验之间的相互作用。已经选择了三类环境暴露，每种都有强烈的流行病学和毒理学文献进行研究：IR，PAHS和OrganoChorines（OCS）。前两个类别（IR和PAH）都会引起DNA损伤，并诱导p53依赖性DNA损伤反应，但DNA损伤机制不同。相比之下，OC不会通过直接损坏DNA来起作用，因此为p53依赖性信号传导提供了阴性对照。 OC还提供了PAHS的比较，因为PAHS和OC可以激活乳房中的芳基烃受体（AHR）和扰动内分泌作用。在AIM 1中，我们将使用等源性人类乳腺细胞系（有或不具有p53RNAI表达以敲除p53表达）和无效TRP53+/+和TRP53 - / - 小鼠的p53依赖性作用。在AIM 2中，我们将检查与人类（使用还原雄性成形术样本）和小鼠相关的基因表达谱，并特别注意鉴定p53调节的基因表达。在AIM 3中，将通过比较对毒性和年龄匹配的无小鼠的毒物的转录反应来评估平等和环境致癌之间的相互作用。对毒物的差异反应将在无效妇女的人类乳腺组织的外植体培养物中得到验证（减少乳腺成形术的多余组织）。因此，每个目标都将整合人类和小鼠的反应以定义对毒物和平等的反应。所有三个目标的数据都将集成，以允许对这些毒物，p53信号传导和平等状态相互作用以影响乳房信号传导及其最终致癌的全面评估。这些研究将定义环境诱导的乳腺癌的机制，并基于定义易感性的基因型 - 表型相关性，并将确定可在未来动物和人类研究中使用的新候选生物标志物。