Perinatal Breast Cancer Programming: fat and estrogens

描述(申请人提供)：这项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、断奶过程中的作用。与人类有关的雌激素暴露的两个来源将被研究：一种以大豆为原料的植物雌激素制剂，主要含有染料木素和大豆苷元，以及普遍存在的环境中的异种雌激素4-壬基苯酚。我们的假设表明，母亲的雌激素环境对成年后乳腺肿瘤的发生风险有很大的影响。2推论是：(A)植物雌激素(90ppm染料木素/大豆苷元)，与具有高n-3/n-6多不饱和脂肪酸平衡的等卡路里20%脂肪饮食相结合，将显著降低乳腺癌的风险；以及(B)异种雌激素暴露(25ppm 4-壬基苯酚)，与低n-3/n-6脂肪酸平衡相结合，将增加患乳腺癌的风险。这一假设将在一种独特的乳腺癌小鼠模型中进行验证，该模型具有肿瘤抑制基因Trp53等位基因条件突变的乳房特异性表达(FLOX‘D p53.R270H/WAP-CRE模型)。这种“人源化”突变等位基因在乳腺上皮细胞中被永久激活，只有在经历了第一个妊娠-哺乳周期的女性才会激活。这种表达使女性在25-52周之间易患乳腺肿瘤(-70%)。该项目有两个并行的具体目标。(1)探讨孕期-新生儿暴露于植物/异种雌激素对雌性后代乳腺发育和肿瘤发生的影响。(2)利用基因表达谱和激光捕获显微切割的强大组合，计数了p53.R270H/WAP-CRE女性幼稚(处女)和启动(胎儿期)乳腺上皮端芽和转移管的分子丰度谱，作为癌前病变的焦点。这些研究将提供基于基因调控网络的新的生物标记物线索，这些网络与改变的胎儿编程和癌前病变相关(或反相关)，并认识到这些网络可能如何在功能上与乳腺癌的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.