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2种雌激素暴露源：主要含有染料木黄酮和大豆苷元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。我们的假设指出，母体雌激素环境对成年后乳腺肿瘤发生的风险有很大的影响。2个推论是：（a）植物雌激素（90 ppm染料木黄酮/大豆苷元），结合具有高n-3/n-6多不饱和脂肪酸平衡的等热量20%脂肪饮食，将显著降低乳腺肿瘤的风险;和（B）异种雌激素暴露（25 ppm 4-壬基酚），结合低饮食n-3/n-6脂肪酸平衡，将增加风险。将在肿瘤抑制基因Trp 53等位基因中具有条件突变的乳腺特异性表达的乳腺癌的独特小鼠模型（flox'd p53.R270H/WAP-Cre模型）中检验该假设。“人源化”突变等位基因在乳腺上皮中被永久激活，仅在经历其第一个妊娠-哺乳周期的女性中。这种表达使年龄在25-52周之间的女性易患乳腺肿瘤（~ 70%发病率）。该项目有两个并行的具体目标。(1)研究妊娠期-新生儿暴露于植物性/异种雌激素对条件性p53.R270 H等位基因杂合子雌性后代乳腺发育和肿瘤发生的影响，这些雌性后代在低和高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，计算上皮端芽和对向导管的分子丰度谱，作为p53. R270 H/WAP-Cre雌性动物的幼稚（处女）和起始（经产）乳腺中癌前病变的病灶。这些研究将提供基于基因调控网络的新的生物标志物线索，这些基因调控网络与改变的胎儿编程和癌前病变相关（或反相关），并认识到这些网络如何在功能上与乳腺癌的产前环境风险因素相关。