Perinatal Breast Cancer Programming--Fat and estrogens

描述（由申请人提供）：本研究的长期目标是研究乳腺癌的胎儿起源以及环境因素在早期发育，受孕-断奶中的作用。将研究与人类相关的两种雌激素暴露来源：一种主要含有染料木素和大豆苷元的大豆植物雌激素制剂，以及普遍存在的环境外源雌激素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的影响。2推论是：(a)植物雌激素（90 PPM染料木素/大豆黄酮），与具有高n-3/n-6多不饱和脂肪酸平衡的20%等热量脂肪饮食相结合，将显著降低乳腺肿瘤的风险；(b)暴露于异雌激素（25 PPM的4-壬基酚），再加上饮食中n-3/n-6脂肪酸平衡过低，会增加患病风险。这一假设将在一种独特的乳腺癌小鼠模型中得到验证，该模型具有肿瘤抑制基因Trp53 （flox'd p53）等位基因条件突变的乳腺特异性表达。R270H / WAP-Cre模型)。“人源化”突变等位基因在乳腺上皮中永久激活，仅在经历第一次怀孕-哺乳周期的女性中激活。这种表达使25-52周龄的女性更易患乳腺肿瘤（发病率-70%）。该项目有两个并行的特定目标。(1)探讨妊娠期和新生儿暴露于植物/异种雌激素对条件p53杂合雌性后代乳腺发育和肿瘤发生的影响。在低和高n-3/n-6脂肪酸组成饲粮中饲养R270H等位基因。(2)利用基因表达谱与激光捕获显微解剖的强大结合，列举上皮终芽和相关导管的分子丰度谱，作为p53在幼稚（处女）和起始（分娩）乳腺中癌前病变的病灶。R270H / WAP-Cre女性。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，这些网络与改变的胎儿编程和恶性肿瘤相关（或反相关），并实现这些网络如何在功能上与乳腺癌产前环境风险因素相关。

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.