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）：本研究的长期目标是调查乳腺癌的胎儿起源以及环境因素在早期发育、受孕断奶过程中的作用。将研究与人类相关的两种雌激素暴露来源：主要含有染料木黄酮和大豆黄酮的大豆植物雌激素制剂，以及普遍存在的环境异雌激素4-壬基酚。我们的假设表明，母亲的雌激素环境对成年后乳腺肿瘤发生的风险有很大影响。 2 个推论是： (a) 植物雌激素（90 ppm 金雀异黄素/大豆黄酮）与具有高 n-3/n-6 多不饱和脂肪酸平衡的等热量 20% 脂肪饮食相结合，将显着降低乳腺肿瘤的风险； (b) 异雌激素暴露（25 ppm 4-壬基酚），加上膳食 n-3/n-6 脂肪酸平衡低，会增加风险。该假设将在一种独特的乳腺癌小鼠模型中进行测试，该模型具有肿瘤抑制因子 Trp53 等位基因条件突变的乳腺特异性表达（flox'd p53.R270H/WAP-Cre 模型）。 “人源化”突变等位基因仅在经历第一个妊娠-哺乳周期的女性的乳腺上皮中永久激活。这种表达使 25-52 周龄女性容易患乳腺肿瘤（-70% 发病率）。该项目有 2 个同时存在的具体目标。 (1) 研究妊娠-新生儿暴露于植物/异种雌激素对条件性 p53.R270H 等位基因杂合子雌性后代乳腺发育和肿瘤发生的影响，该杂合子在低和高 n-3/n-6 脂肪酸组成的饮食中饲养。 (2) 使用基因表达谱与激光捕获显微切割的强大组合，列举了上皮终芽和包覆导管的分子丰度谱，作为 p53.R270H/WAP-Cre 雌性的幼稚（处女）和起始（经产）乳腺癌前变化的焦点。这些研究将提供基于基因调控网络的新生物标志物线索，这些网络与胎儿编程改变和癌前病变相关（或反相关），并认识到这些网络如何与乳腺癌的产前环境风险因素在功能上相关。