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）： 在流行病学文献中，乳腺癌与环境致癌物暴露之间的关联往往很弱或不一致，即使存在强有力的实验数据。对环境致癌作用的最有力支持来自小鼠模型，该模型显示电离辐射（IR）和多环芳烃（PAH）等暴露会增加乳腺肿瘤的形成。这些相同的实验模型已经表明，奇偶性具有p53介导的对致癌作用的保护作用。本申请提出了一种比较毒理学方法，用于解剖导致乳腺环境致癌的生物学途径，重点是环境致癌物，p53途径和奇偶性之间的相互作用。三类环境暴露，每一个强大的流行病学和毒理学文献，已被选定为研究：IR，多环芳烃和有机氯（OC）。前两类（IR和PAHs）都能引起DNA损伤，并诱导p53依赖的DNA损伤反应，但损伤机制不同。相反，OC不通过直接损伤DNA起作用，因此为p53依赖性信号传导提供阴性对照。有机化合物还提供了多环芳烃的比较，因为多环芳烃和有机化合物都可以激活芳烃受体（AhR），扰乱乳腺内分泌活动。在目标1中，我们将使用等基因人乳腺细胞系（有和没有表达p53 RNAi以敲低p53表达）和未经产Trp 53 +/+和Trp 53-/-小鼠评估每种毒物的p53依赖性效应。在目标2中，我们将研究人类（使用乳房缩小术样本）和小鼠中与产次相关的基因表达谱，特别注意识别p53调控的基因表达。在目标3中，将通过比较经产和年龄匹配的未经产小鼠对毒物的转录反应来评估产次和环境致癌作用之间的相互作用。将在来自未经产和经产女性的人乳腺组织（来自乳房缩小术的多余组织）的外植体培养物中验证对毒物的不同反应。因此，每个目标将整合人类和小鼠的反应，以定义对毒物和奇偶性的反应。来自所有三个目标的数据将被整合，以允许对环境暴露于这些毒物、p53信号传导和奇偶校验状态如何相互作用以影响乳腺信号传导并最终致癌进行完整的多因素评估。这些研究将确定环境诱导的乳腺癌的机制，锚定在定义易感性的基因型-表型相关性上，并将确定可用于未来动物和人类研究的新的易感性候选生物标志物。