Disruption of parity-induced tumor suppressor pathways by xenoestrogen exposures

 描述（由申请人提供）：奇偶性参与乳腺上皮内的通路，使其对致癌作用具有抗性。这些途径是有效的，因为奇偶性降低了与致癌物和遗传风险等位基因相关的风险，每年预防多达70，000例乳腺癌。怀孕期间雌激素的水平足以模拟产次的保护作用。雌激素的作用由两种雌激素受体亚型（ERα和ERβ）介导，这两种亚型平衡了它们对p53肿瘤抑制途径介导的增殖和生长抑制的竞争作用。妊娠还抑制WNT/β-连环蛋白信号传导，并减少乳腺上皮内脆弱干细胞的库。然而，长期暴露于外源性雌激素侵蚀啮齿动物妊娠的保护作用。妊娠期间，女性暴露于高水平的异种雌激素（二苯甲酮、对羟基苯甲酸酯、邻苯二甲酸酯），这些雌激素对ERα和ERβ的效力不同。因此，妊娠是一个关键窗口，在此期间，异种雌激素可能会破坏肿瘤抑制途径，使乳腺上皮细胞对致癌作用敏感。 在这些实验中，我们将检测4种在孕妇中含量丰富且对ERα和ERβ的效力不同的异种雌激素。在原代乳腺组织和小鼠模型中的平行实验用于确定异种雌激素是否干扰妊娠对关键肿瘤抑制途径的影响。具体目标1将使用乳腺上皮细胞来确定异种雌激素对肿瘤抑制途径的影响以及女性反应的变化。将在表达ERα或ERα+ERβ的MCF-7乳腺癌细胞中确定每种异种雌激素的剂量-反应关系。正常乳腺上皮细胞的原代培养物将用于确认反应并确定对异种雌激素高度敏感或耐药的女性亚群。具体目标2比较了异种雌激素在乳腺组织外植体培养物和BALB/c小鼠中的作用。原代乳腺外植体更忠实地反映了乳腺组织内的信号传导和来自Aim 1的补充结果。对雌激素特别敏感的小鼠（BALB/c）的平行治疗将验证体内模型，并确定长期暴露于异种雌激素对肿瘤抑制途径的影响。具体目标3将测试异种雌激素对肿瘤发生的影响。将使用CDβGeo细胞移植物检测异种雌激素引起癌前细胞进展的能力。将在携带Trp 53 +/-乳腺上皮移植物的小鼠中检测异种雌激素逆转产次保护作用的能力。社区参与：社区合作伙伴提供了一种动态传达社区关注和研究结果的手段。重要的是，这些实验旨在确定可能特别容易受到异种雌激素影响的女性子集，并证明小鼠模型与人类暴露的相关性。

 DESCRIPTION (provided by applicant): Parity engages pathways within the breast epithelium that render it resistant to carcinogenesis. These pathways are potent as parity reduces the risk associated with carcinogens and inherited risk alleles preventing as many as 70,000 cases of breast cancer annually. The levels of estrogens during pregnancy are sufficient to mimic the protective effects of parity. The actions of estrogens are mediated by two estrogen receptor subtypes (ERα and ERβ) that balance their competing effects on proliferation and growth suppression mediated by the p53 tumor suppressor pathway. Pregnancy also suppresses WNT/β-catenin signaling and reduces the pool of vulnerable stem cells within the mammary epithelium. However, chronic exposure to exogenous estrogens erodes the protective effects of pregnancy in rodents. During pregnancy, women are exposed to high levels of xenoestrogens (benzophenones, parabens, phthalates) that differ in their potencies for ERα and ERβ. Therefore, pregnancy is a critical window during which xenoestrogens may disrupt tumor suppressor pathways and render the breast epithelium susceptible to carcinogenesis. In these experiments, we will test 4 xenoestrogens that are abundant in pregnant women and differ in potency for ERα and ERβ. Parallel experiments in primary breast tissues and mouse models are used to determine if xenoestrogens interfere with the effects of pregnancy on critical tumor suppressor pathways. Specific Aim 1 will use breast epithelial cells to determine the effects of xenoestrogens on tumor suppressor pathways and the variation in responses among women. Dose-response relationships for each xenoestrogen will be determined in MCF-7 breast cancer cells expressing either ERα or both ERα+ERβ. Primary cultures of normal breast epithelial cells will be used to confirm responses and define subsets of women who are highly sensitive or resistant to xenoestrogens. Specific Aim 2 compares effects of xenoestrogens in explant cultures of breast tissue and in BALB/c mice. Primary breast explants more faithfully reflect signaling within breast tissue and complement results from Aim 1. Parallel treatments in mice that are particularly sensitive to estrogens (BALB/c) will validate the in vivo model and determine effects of chronic exposures to xenoestrogens on tumor suppressor pathways. Specific Aim 3 will test the effects of xenoestrogens on tumorigenesis. The ability of xenoestrogens to cause progression of premalignant cells will be tested using transplants of CDβGeo cells. The ability of xenoestrogens to reverse the protective effect of parity will be tested in mice bearing transplants of Trp53+/- mammary epithelium. Community Engagement: The Community Partners provide a means to dynamically communicate the concerns of the community and results from research. Importantly, the experiments are designed to identify a subset of women who may be especially vulnerable to xenoestrogens and demonstrate the relevance of the mouse models to human exposures.