PCBs: Environmental Modulators of Human Breast Cancer Progression

乳腺癌的发展是遗传风险和环境暴露的结果。 多氯联苯(多氯联苯)是环境污染物，尽管它们被禁止使用，但代表着 由于它们在乳房等富含脂肪的组织中的持久性，对人类的持续威胁。剖析印刷电路板基因-- 环境相互作用，有必要了解多氯联苯的作用机制 增强乳腺癌的致癌作用。多氯联苯是化学和毒理上不同的分子，与平面多氯联苯一样。 激活芳香烃受体，而非平面多氯联苯激活替代的异种生物传感 感受器。许多多氯联苯的同系物能够发挥雌激素效应和/或诱导氧化应激。 某些多氯联苯被生物转化为羟化的代谢物，这可以进一步传播氧化应激。 和/或雌激素效应。例如，虽然一些羟化的多氯联苯是雌激素受体(ER)配体， 其他是雌激素磺基转移酶的有效抑制剂，雌激素磺基转移酶是人体内主要的雌激素失活酶。 乳腺上皮细胞。多氯联苯治疗的效果从未在人体活体模型中进行过评估 乳腺癌的进展。MCF10AT1肿瘤前病变皮下移植模型的建立 人类乳腺上皮细胞形成的病变逐渐向肿瘤发展，提供了一种独特的 有机会剖析多氯联苯在体内影响人类乳腺癌进展的机制。这个 这一提议的假设是，不同类别的多氯联苯加速了乳腺癌前病变的进展 上皮细胞转化为持续性病变，代表更晚期的恶变。这个 不同种类的多氯联苯对异种移植进展的影响反映了它们的相对能力：(1)发挥促进作用； 雌激素效应和(2)诱导氧化应激。具体目标1将确定多氯联苯处理的效果 它们是(1)平面多氯联苯、(2)非平面多氯联苯和(3)羟基多氯联苯代谢物的原型 人乳腺肿瘤在MCF10AT1异种移植模型中的形成具体目标2将决定印刷电路板是否- 对人类乳腺肿瘤发生的中介作用是通过(1)ER依赖，(2)氧化应激- 依赖和/或(3)细胞色素P450代谢依赖机制。这些研究将带来新的曙光。 关于多氯联苯改变乳腺组织动态平衡以促进肿瘤形成的核心机制。乳腺癌的发展是遗传风险和环境暴露的结果。 多氯联苯(多氯联苯)是环境污染物，尽管它们被禁止使用，但代表着 由于它们在乳房等富含脂肪的组织中的持久性，对人类的持续威胁。然而，它的影响 多氯联苯从未在人体乳腺癌进展的活体模型中被评估过。这些研究将 采用独特的人类乳腺癌进展模型，通过以下方式揭示乳腺癌的核心机制 哪些环境中的多氯联苯促进癌症的发展。

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.