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（由申请人提供）：本申请的主要目的是确定异雌激素物质双酚A（BPA）和邻苯二甲酸丁基苄酯（BBP）是否在人类乳腺癌的发生中发挥作用，如果是的话，这种作用是否是由表观遗传机制介导的。这项拟议的研究是基于人们日益担心，作为内分泌干扰化学物质的雌激素环境化合物可能会对乳房等激素敏感器官产生潜在的不利影响。有证据表明天然雌激素，即 17β-雌二醇 (E2)，是乳腺癌发生和进展的重要因素，进一步加剧了这种担忧。因此，人们担心具有雌激素特性并在环境中广泛分布的 BPA 和 BBP 也可能对人类乳房致癌，这是有道理的。为了实现这些目标，我们将利用我们的体外体内模型，在该模型中我们已经证明了 E2 在人乳腺上皮细胞 MCF-10F 中的致癌性。利用这种强大而独特的模型将为我们提供一个工具来探索 BPA 和 BBP 是否与乳腺癌的发生相关。此外，我们发现E2诱导的转化表型的表达与控制分支和导管发生的基因的高甲基化或低甲基化有关。这些是我们假设异雌激素 BPA 和 BBP 可以通过作为表观遗传调节剂诱导肿瘤转化的基础，通过高甲基化和/或组蛋白修饰诱导关键基因沉默，从而导致乳腺癌的发生和进展。为此，我们提出以下具体目标：确定异雌激素 BPA 和 BBP 是否诱导人乳腺上皮细胞的肿瘤转化，以及转化表型的表达是否与控制分支和导管发生的基因的表观遗传变化相关，如果是这种情况，确定修改其甲基化状态是否可以逆转肿瘤过程。为了实现这一目标，我们将使用 MCF-10F 细胞和从乳房缩小成形术中获得的人乳腺上皮细胞的原代培养物。将使用 BPA 和 BBP 处理细胞，使用的方案类似于用 E2 处理这些细胞所用的方案，E2 将作为对照。将使用限制性地标基因组扫描 (RLGS) 进行甲基化研究，并将使用甲基化特异性 PCR (MSP) 进一步研究已识别的基因，然后确认其表达和功能作用。总而言之，这些研究将为异雌激素物质是否能够诱导 HBEC 肿瘤转化以及表观遗传机制参与这一过程提供第一手证据。此外，操纵甲基化状态和沉默这些表观遗传修饰基因不仅可以让我们了解这些环境污染物如何参与乳腺癌的发生，还可以为我们提供制定预防策略以抵消其对普通人群影响的工具。与公众健康的相关性：这些研究将为 BPA 和 BBP 等异雌激素物质是否能够诱导 HBEC 肿瘤转化以及该过程涉及表观遗传机制提供第一手证据。此外，操纵甲基化状态和沉默这些表观遗传修饰基因不仅可以了解这些广泛的环境污染物如何参与乳腺癌的发生，而且可以制定预防策略来抵消它们对普通人群的影响。

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.