Epigenetic Changes Induced by Estrogens and Xenoestrogens in Breast Cancer

雌激素和异雌激素在乳腺癌中引起的表观遗传变化

• 批准号: 7492179
• 负责人: JOSE RUSSO
• 金额: $ 20.95万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492179
• 关键词: Adverse effects; Affect; Anchorage-Independent Growth; Atypia; Atypical hyperplasia; Breast; Cells; Collagen; Condition; DNA Methylation; Data; Endocrine Disruptors; Endocrine disruption; Endocrine system; Environment; Environmental Pollution; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Estradiol; Estrogens; Gene-Modified; General Population; Genes; Genetic; Genomics; Goals; Hand; Histone Code; Histones; Hormonal; Hormones; Human; Hypermethylation; Hyperplasia; In Vitro; Invasive; Knowledge; Lead; Malignant Neoplasms; Mediating; Methylation; Modeling; Modification; Neoplastic Cell Transformation; Neoplastic Processes; Noninfiltrating Intraductal Carcinoma; Organ; Pattern; Personal Satisfaction; Phenotype; Play; Polymerase Chain Reaction; Prevention strategy; Primary Cell Cultures; Process; Property; Protocols documentation; Public Health; Purpose; Pyrenes; Role; SCID Mice; Scanning; Staging; System; Tissues; base; bisphenol A; breast lesion; butylbenzyl phthalate; carcinogenicity; cell transformation; in vivo Model; malignant breast neoplasm; matrigel; pyrene; tool; tumorigenesis; xenoestrogen

DESCRIPTION (provided by applicant): The main objective of this application is to determine whether the xenoestrogenic substances bisphenol A (BPA) and butyl benzyl phthalate (BBP) play a role in the initiation of human breast cancer, and if so, whether this effect is mediated by epigenetic mechanisms. The proposed study is based on the growing concern that estrogenic environmental compounds that act as endocrine disrupting chemicals might have potential adverse effects on hormone-sensitive organs such as the breast. This concern is further fueled by evidence indicating that natural estrogens, namely 17 ¿-estradiol (E2), are important factors in the initiation and progression of breast cancer. Therefore, the concern that BPA and BBP, which have estrogenic properties and are widely distributed in the environment, might also be carcinogenic for the human breast is well justified. For accomplishing these goals we will utilize our in vitro in vivo model in which we have demonstrated the carcinogenicity of E2 in the human breast epithelial cells MCF-10F. The utilization of this powerful and unique model will provide us a tool for exploring whether BPA and BBP have relevance in the initiation of breast cancer. Furthermore, we have found that the expression of E2-induced transformation phenotypes is associated with hyper or hypomethylation of genes controlling branching and ductulogenesis. These are the basis for our rationale to postulate that the xenoestrogens BPA and BBP can induce neoplastic transformation by behaving as epigenetic modulators inducing silencing of critical genes by hypermethylation and/or histone modification that lead to the initiation and progression of breast cancer. For this purpose, we propose the following specific aim: To determine whether the xenoestrogens BPA and BBP induce neoplastic transformation in human breast epithelial cells and whether the expression of transformation phenotypes is associated with epigenetic changes in genes controlling branching and ductulogenesis, and if this is the case, to determine if modifying their methylation status reverts the neoplastic process. To accomplish this aim we will use MCF-10F cells and primary cultures of human breast epithelial cells obtained from reduction mammoplasty. The cells will be treated with BPA and BBP using a protocol similar to that used for the treatment of these cells with E2, which will serve as a control. Methylation studies will be performed using Restriction Landmark Genomic Scanning (RLGS) and the identified genes will be further studied using methylation specific PCR (MSP) followed by confirmation of their expression and functional role. Altogether, these studies will provide first hand evidence on whether xenoestrogenic substances are able to induce neoplastic transformation in HBEC and that epigenetic mechanisms are involved in this process. Furthermore the manipulation of the methylated status and silencing of those epigenetically modified genes will provide not only an understanding of how these environmental contaminants are involved in breast cancer initiation but also will give us tools for developing preventive strategies to counteract their effect in the general population. RELEVANCE TO PUBLIC HEALTH: These studies will provide first hand evidence on whether xenoestrogenic substances like BPA and BBP are able to induce neoplastic transformation in HBEC and that epigenetic mechanisms are involved in this process. Furthermore the manipulation of the methylated status and silencing of those epigenetically modified genes will provide not only an understanding how these widely environmental contaminants are involved in breast cancer initiation but also for developing preventive strategies to counteract their effect in the general population.

描述（通过应用程序提供）：本应用的主要目的是确定异源性物质Bisphenol A（BPA）（BPA）和苯甲酸丁酯（BBP）是否在人类乳腺癌的开始中起作用，如果是这样，是否由表观遗传学机制介导。拟议的研究基于越来越关注的是，充当内分泌化学物质的雌激素环境化合物可能会对乳房等马敏感器官（例如乳房）产生潜在的不利影响。证据表明天然雌激素（即17 - 雌二醇（E2））是乳腺癌启动和进展的重要因素。因此，担心具有雌激素并且在环境中广泛分布的BPA和BBP也可能是人类乳房的致癌性。为了完成这些目标，我们将利用我们的体外体内模型，其中我们已经证明了人类乳腺上皮细胞MCF-10F中E2的致癌性。这种强大而独特的模型的利用将为我们提供一种工具，用于探索BPA和BBP是否与乳腺癌的开始是否相关。此外，我们发现E2诱导的转化表型的表达与控制分支和公关基因的基因的高或甲基化有关。这些是我们理由假设异源性雌激素BPA和BBP可以通过表观遗传调节剂来诱导肿瘤转化的基础，从而通过表观遗传调节剂来通过高甲基化和/或组蛋白修饰引起关键基因的沉默，从而导致乳腺癌的启动和进展。为此，我们提出了以下具体目的：确定异种雌激素BPA和BBP在人乳房上皮细胞中诱导肿瘤转化，以及转化表型的表达是否与控制分支和duculogenogeny的基因的表观遗传变化相关，以确定是否可以修改其甲基化状态。为了实现这一目标，我们将使用从还原乳腺成形术获得的MCF-10F细胞和原发性培养物。将使用类似于用E2处理这些细胞的方案，用BPA和BBP处理细胞，该方案将作为对照。甲基化研究将使用限制性地标基因组扫描（RLGS）进行，并将使用甲基化特异性PCR（MSP）进一步研究确定的基因，然后确认其表达和功能作用。总的来说，这些研究将提供第一手证据，证明异雌激素物质是否能够诱导HBEC中的肿瘤转化，并且表观遗传机制参与了这一过程。此外，操纵甲基化状态和对这些表观遗传修饰的基因的沉默不仅会提供对这些环境污染物如何参与乳腺癌启动的理解，而且还将为我们提供开发预防策略来抵消其在普通人群中的作用的工具。与公共卫生的相关性：这些研究将提供第一手证据，表明诸如BPA和BBP（BBP）是否能够诱导HBEC中的肿瘤转化，并且表观遗传机制参与此过程。此外，操纵甲基化状态和对这些表观遗传修饰的基因的沉默将不仅提供理解这些广泛环境​​污染物如何参与乳腺癌开始，还可以制定预防策略以抵消其对普通人群的影响。

项目成果

Estrogen induced breast cancer is the result in the disruption of the asymmetric cell division of the stem cell.

雌激素诱发的乳腺癌是干细胞不对称细胞分裂破坏的结果。

• DOI: 10.1515/hmbci.2010.011
• 发表时间: 2010
• 期刊: Hormone molecular biology and clinical investigation
• 影响因子: 1
• 作者: Russo,Jose;Snider,Kara;Pereira,JuliaS;Russo,IrmaH
• 通讯作者: Russo,IrmaH

Progressive increase of glucose transporter-3 (GLUT-3) expression in estrogen-induced breast carcinogenesis.

• DOI: 10.1007/s12094-012-0882-3
• 发表时间: 2013-01
• 期刊: CLINICAL & TRANSLATIONAL ONCOLOGY
• 影响因子: 3.4
• 作者: Kocdor, M. A.;Kocdor, H.;Pereira, J. S.;Vanegas, J. E.;Russo, I. H.;Russo, J.
• 通讯作者: Russo, J.