Perinatal Breast Cancer Programming: fat and estrogens

围产期乳腺癌规划：脂肪和雌激素

• 批准号: 7082042
• 负责人: Thomas B Knudsen
• 金额: $ 12.45万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082042
• 关键词: animal genetic material tag; bioinformatics; breast neoplasms; cancer risk; developmental disease /disorder; dietary lipid; early experience; embryo /fetus; estrogens; gas chromatography mass spectrometry; gene expression profiling; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; laser capture microdissection; longitudinal animal study; mammary epithelium; microarray technology; molecular oncology; mother /embryo /fetus nutrition; nutrition related tag; phytoestrogens; placental transfer; polymerase chain reaction; tumor promoters

DESCRIPTION (provided by applicant): The long-term goal of this research is to investigate the fetal origins of breast cancer and the role of environmental factors during early development, conception-weaning. 2 sources of estrogenic exposure relevant to man will be studied: a phytoestrogen preparation from soy mainly containing genistein and daidzein, and the ubiquitous environmental xenoestrogen 4-nonylphenol. Our hypothesis states the maternal estrogenic environment has a strong influence on risk to mammary tumorigenesis in adult life. 2 corollaries are: (a) phytoestrogens (90 ppm genistein/daidzein), in conjunction with an isocaloric 20% fat-diet having high n-3/n-6 polyunsaturated fatty acid balance, will significantly lower the risk of mammary tumors; and (b) xenoestrogen exposure (25 ppm 4-nonylphenol), in conjunction with a low dietary n-3/n-6 fatty acid balance, will promote the risk. The hypothesis will be tested in a unique mouse model for breast cancer having mammary-specific expression of a conditional mutation in the tumor suppressor Trp53 allele (flox'd p53.R270H/WAP-Cre model). The "humanized" mutant allele is permanently activated in the mammary gland epithelium exclusively in females traversing their first pregnancy-lactation cycle. This expression predisposes females to mammary tumors (-70% incidence) between ages 25-52 weeks. The project has 2 concurrent Specific Aims. (1) To investigate the effects of gestational-neonatal exposure to phyto/xenoestrogens on mammary gland development and tumorigenesis in female offspring heterozygous for the conditional p53.R270H allele reared on diets of low and high n-3/n-6 fatty acid composition. (2) Using the powerful combination of gene expression profiling with laser capture microdissection enumerate the molecular abundance profiles of epithelial end-buds and subtending ducts as foci for pre-malignant changes in the naive (virgin) and initiated (parous) mammary gland of p53.R270H/WAP-Cre females. These studies will provide new biomarker leads based in genetic regulatory networks that correlate (or anti-correlate) with altered fetal programming and pre-malignancy together with the realization of how such networks might relate functionally to the prenatal environmental risk factors in breast cancer.

描述（由申请人提供）：这项研究的长期目标是研究乳腺癌的胎儿起源以及在早期发育中的环境因素的作用。将研究2种与人有关的雌激素暴露来源：主要含有大豆的植物雌激素制剂，主要含有染料蛋白酶和大豆，以及无处不在的环境静态雌激素4-北苯酚。我们的假设指出，孕产妇雌激素环境对成人生活中乳腺肿瘤发生的风险有很大的影响。 2个推论为：（a）植物雌激素（90 ppm染料蛋白酶/大麦氏蛋白酶），以及具有高N-3/N-6多不饱和脂肪酸平衡的等分系数20％脂肪含量，将显着降低乳腺肿瘤的风险； （b）异源性雌激素暴露（25 ppm 4-氯苯醇）与饮食中的N-3/N-6脂肪酸平衡相同，将促进风险。该假设将在唯一的小鼠模型中检验，用于在肿瘤抑制器TRP53等位基因中具有条件突变的乳腺癌表达（Flox'D p53.r270h/wap-cre模型）。 “人性化”突变等位基因在乳腺上皮中永久激活，仅在遍历其第一个妊娠乳酸周期的女性中。这种表达使女性容易受到25-52周之间的乳腺肿瘤（-70％发病率）。该项目具有2个并发的特定目标。 （1）研究妊娠 - 神经膜暴露于植物/异种雌激素对有条件的p53.r270h等位基因的雌性后代杂合的乳腺发育的影响和肿瘤发生的影响，该等位基因是在低和高N-3/N-6-6脂肪酸组成的饮食中饲养的。 （2）使用基因表达谱分析与激光捕获显微解剖的强大组合列举了上皮终端终止终止和替代导管的分子丰富度谱图，作为幼稚（Virgin）（Virgin）和启动（Parous）p53.r270H/wap-wap-cre女性的乳腺（parous）乳腺（parous）乳腺的抗性变化的焦点。这些研究将为基于遗传调节网络的新生物标志物提供与胎儿程序的改变（或抗逆转录），以及实现此类网络如何与乳腺癌中乳腺癌产前环境风险因素相关联的遗传调节网络。