MAMMARY CELL SIGNALING PRODUCED BY ENVIRONMENTAL AGENTS

在美国和其他国家，乳腺癌的发病率一直在上升 多年来一直在各个国家工作。虽然没有得到证实的解释 疾病风险增加。看来，环境和饮食 这些因素可能在乳腺癌的发生发展中起着重要作用。这个 这项建议的目的是审查环境的影响 与乳腺上皮细胞生长和信号转导相关的化学物质 内源性生长因子受体。据推测，环境问题 而饮食制剂可能会扰乱正常的生长因子信号传递过程， 或在低剂量时，实际上可能模仿内源生长产生的信号 各种因素。对内源性生长因子的反应改变可能起到 在乳腺癌的发生发展中起着重要作用。我们将重点关注两个方面 一类重要的环境试剂，称为多环芳烃 碳氢化合物(PAHs)和卤代芳香烃(HAHS) 存在于空气中的各种排放物和饮食中。多环芳烃已经被 PI显示显著改变钙依赖的细胞信号转导 人类B和T淋巴细胞，以及最近的研究表明，钙离子 人乳腺上皮细胞中的信号对 被多环芳烃激活。由于HAHS可能与PAHs共享物业，我们将 检查这类重要的环境污染物(包括 二恶英、多氯联苯和复杂混合物)。我们会研究 多环芳烃是动物中众所周知的乳腺癌致癌物质，而HAHS是 疑似肿瘤促进剂。初步研究表明，在人类 多环芳烃对钙稳态有重要影响的淋巴样细胞系 通过激活与细胞信号相关的酶(蛋白质酪氨酸 激酶)以及参与细胞内钙离子调节的那些 动态平衡(钙-ATPase)。其中许多相同类型的酶在 淋巴细胞也存在于人的乳腺上皮细胞中。因此，它是 可能是乳腺上皮细胞蛋白酪氨酸激酶(EGFR，IGF-1R， 和HER-2/erbB-2)被多环芳烃激活。细胞内钙离子的测量 将使用荧光钙离子螯合剂(Fluo-3)通过流动获得 细胞计数和共聚焦成像。我们还将研究多环芳烃的影响 和HAHS对人乳腺细胞株和人乳腺细胞系中环磷酸腺苷信号通路的影响 乳腺上皮细胞原代培养。雌激素和雌激素的影响 抗雌激素化学物质对PAH和HAH诱导的信号转导也将 探索过了。这些研究的结果将提供重要的新的 关于乳房模仿或调节的潜在机制的信息 上皮细胞生长因子受体与钙信号转导 环保人员。

The incidence of breast cancer has been increasing in the U.S. and other countries for many years. While there is no proven explanation for this increased risk of disease. it appears that environmental and dietary factors may play an important role in breast cancer development. The purpose of this proposal is to examine the influence of environmental chemicals on breast epithelial cell growth and signaling associated with endogenous growth factor receptors. It is hypothesized that environmental and dietary agents may disrupt normal growth factor signaling processes, or at low doses may actually mimic signals generated by endogenous growth factors. Altered responses to endogenous growth factors may play an important role in breast cancer development. We will focus on two important class of environmental agents known as polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) that are present in the air from various emissions and in the diet. PAHs have been shown by the PI to dramatically alter Ca2+-dependent cell signaling in human B and T lymphocytes, and recent studies demonstrate that Ca2+ signaling in human breast epithelial cells is extremely sensitive to activation by PAHs. Since HAHs share may properties with PAHs, we will examine this important class of environmental pollutants (including dioxins, PCBs, and complex mixtures) in this application. We will study PAHs that are well known mammary carcinogens in animals, and HAHs that are suspected tumor promoters. Preliminary studies have shown in human lymphoid cell lines that PAHs exert important effects on Ca2+ homeostasis via activation of enzymes associated with cell signaling (protein tyrosine kinases) as well as those involved in regulation of intracellular Ca2+ homeostasis (Ca2+-ATPase). Many of these same types of enzymes found in lymphocytes also occur in human breast epithelial cells. Therefore, it is likely that breast epithelial cell protein tyrosine kinases (EGFR, IGF-1R, and HER-2/erbB-2) are activated by PAHs. Intracellular Ca2+ measurements will be obtained using fluorescent Ca2+ chelating agents (Fluo-3) via flow cytometry and confocal imaging. We will also examine the influence of PAHs and HAHs on cyclic AMP signaling pathways in human breast cell lines and primary breast epithelial cell cultures. The influence of estrogenic and anti-estrogenic chemicals on PAH and HAH-induced signaling will also be explored. The results of these studies will provide important new information on potential mechanisms of mimicry or modulation of breast epithelial cell growth factor receptors and Ca2+ signaling produced by environmental agents.