PCBs: Environmental Modulators of Human Breast Cancer Progression

PCB：人类乳腺癌进展的环境调节剂

• 批准号: 7851056
• 负责人: Melissa A Runge-Morris
• 金额: $ 19万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851056
• 关键词: Acetylcysteine; Affect; Animals; Antioxidants; Aryl Hydrocarbon Receptor; Breast; CYP1A1 gene; CYP1B1 gene; Catalysis; Cell Culture Techniques; Cells; Cytochrome P450; Data; Development; Dose; Environmental Exposure; Environmental Pollution; Enzymes; Epithelial Cells; Estrogen Receptor 1; Estrogen Receptors; Estrogen Sulfotransferase Inhibitor; Estrogens; Estrone sulfotransferase; Genetic; Genetic Risk; Half-Life; Histology; Homeostasis; Human; Human Milk; ICI 182780; Immunodeficient Mouse; Implant; Individual; Lesion; Life; Ligands; Light; Lipids; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mediating; Metabolism; Modeling; Mus; Neoplasms; Neoplastic Cell Transformation; Oxidative Stress; Patients; Physiological; Play; Polychlorinated Biphenyls; Population Study; Predisposition; Premalignant; Production; Relative (related person); Research; Role; Staging; Stimulation of Cell Proliferation; Testing; Tissues; Xenobiotics; Xenograft Model; Xenograft procedure; aryl hydrocarbon receptor ligand; breast tumorigenesis; carcinogenesis; constitutive androstane receptor; gene environment interaction; in vivo; in vivo Model; indexing; inhibitor/antagonist; malignant breast neoplasm; pregnane X receptor; prototype; receptor; research study; sulfotransferase SULT1E1; treatment effect; tumor progression

The development of breast cancer is a consequence of genetic risks and environmental exposures. Polychlorinated biphenyls (PCBs) are environmental contaminants that, despite their banned use, represent ongoing threats to humans due to their persistence in lipid-rich tissues, such as breast. To dissect PCB gene- environment interactions, it is necessary to gain an understanding of the mechanisms by which PCBs can act to enhance breast carcinogenesis. PCBs are chemically and toxicologically diverse molecules, as planar PCBs activate the aryl hydrocarbon receptor, while non-planar PCBs activate alternative xenobiotic-sensing receptors. Many PCB congeners are capable of exerting estrogenic effects and/or inducing oxidative stress. Certain PCBs are biotransformed to hydroxylated metabolites, which can further propagate oxidative stress and/or estrogenic effects. For example, while some hydroxylated PCBs are estrogen receptor (ER) ligands, others are potent inhibitors of estrogen sulfotransferase, the major estrogen-inactivating enzyme in human breast epithelial cells. The effects of PCB treatments have never been evaluated in an in vivo model of human breast cancer progression. The MCF10AT1 xenograft model, in which subcutaneously implanted preneoplastic human breast epithelial cells form lesions that progressively advance toward neoplasia, provides a unique opportunity to dissect the mechanisms by which PCBs affect human breast cancer progression in vivo. The hypothesis of this proposal is that PCBs of different classes accelerate the progression of pre-malignant breast epithelial cells to persistent lesions that represent more advanced stages of malignant transformation. The effects of different classes of PCBs on xenograft progression reflect their relative abilities to (1) exert pro- estrogenic effects and (2) induce oxidative stress. Specific aim 1 will define the effects of treatments with PCBs that are prototypes of (1) the planar PCBs, (2) the non-planar PCBs and (3) hydroxylated PCB metabolites on human breast tumorigenesis in the MCF10AT1 xenograft model. Specific aim 2 will determine whether PCB- mediated effects on human breast tumorigenesis are mediated through (1) ER-dependent, (2) oxidative stress- dependent and/or (3) cytochrome P450 metabolism-dependent mechanisms. These studies will shed new light on the core mechanisms by which PCBs shift breast tissue homeostasis toward advancing neoplasia. The development of breast cancer is a consequence of genetic risks and environmental exposures. Polychlorinated biphenyls (PCBs) are environmental contaminants that, despite their banned use, represent ongoing threats to humans due to their persistence in lipid-rich tissues, such as breast. However, the effects of PCBs have never been evaluated in an in vivo model of human breast cancer progression. These studies will employ a unique model of human breast cancer progression to shed new light on the core mechanisms by which environmental PCBs promote cancer development.

乳腺癌的发展是遗传风险和环境暴露的结果。 多氯联苯（PCB）是环境污染物，尽管使用了它们，但它们代表 由于人类在富含脂肪的组织中的持续存在，例如乳房，对人类的持续威胁。剖析PCB基因 环境相互作用，有必要了解PCB可以采取的机制 增强乳腺癌的发生。 PCB在化学和毒理学上是多样的分子，作为平面PCB 激活芳基碳氢化合物受体，而非平面PCB激活替代性异生物敏感性 受体。许多PCB同源物能够发挥雌激素作用和/或诱导氧化应激。 某些PCB对羟基化代谢产物进行生物转化，这可以进一步传播氧化应激 和/或雌激素作用。例如，虽然一些羟基化PCB是雌激素受体（ER）配体，但 其他是雌激素磺胺转移酶的有效抑制剂，这是人类的主要雌激素灭活酶 乳房上皮细胞。 PCB治疗的影响从未在人体的体内模型中进行评估 乳腺癌的进展。 MCF10AT1异种移植模型，其中皮下植入前塑性塑料 人类乳房上皮细胞形成病变，逐渐朝着肿瘤前进，提供了独特的病变 剖析PCB的机制影响人类乳腺癌进展的机会。这 该提议的假设是不同类别的PCB加速了乳房前乳房的进展 上皮细胞到持续性病变，代表了恶性转化的更高级阶段。这 不同类别的PCB对异种移植进展的影响反映了其相对能力（1）发挥作用 雌激素作用和（2）诱导氧化应激。特定目标1将定义PCB处理的影响 是（1）平面PCB的原型，（2）非平面PCB和（3）在 MCF10AT1异种移植模型中的人类乳腺肿瘤发生。特定的目标2将确定PCB是否是否 通过（1）ER依赖性，（2）氧化应激 - 依赖和/或（3）细胞色素P450代谢依赖性机制。这些研究将使新的光芒 PCB的核心机制将乳腺组织稳态转向推进肿瘤。乳腺癌的发展是遗传风险和环境暴露的结果。 多氯联苯（PCB）是环境污染物，尽管使用了它们，但它们代表 由于人类在富含脂肪的组织中的持续存在，例如乳房，对人类的持续威胁。但是， PCB从未在人类乳腺癌进展的体内模型中进行评估。这些研究会 采用人类乳腺癌进展的独特模型，通过 哪种环境PCB促进了癌症的发展。