Effect of bisphenol A exposure on mammary stem cell function and transformation

双酚A暴露对乳腺干细胞功能和转化的影响

• 批准号: 8843434
• 负责人: LUZHE SUN
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843434
• 关键词: Adverse effects; Affect; Animals; Beverages; Breast Cancer Risk Factor; Callithrix; Callithrix jacchus jacchus; Carcinoma in Situ; Cell Count; Cell physiology; Cell surface; Chemicals; DNA Damage; DNA Repair; Development; Diet; Dose; Epoxy Resins; Exposure to; Food; Frequencies; Gene Expression Profile; Growth; Human; Incidence; Intraductal Hyperplasia; Ionizing radiation; Laboratories; Lead; Life; Light; Link; Longevity; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Morphogenesis; Mus; Neoplastic Cell Transformation; Obese Mice; Obesity; Perinatal Exposure; Phylogenetic Analysis; Physiological; Pit and Fissure Sealants; Play; Predisposition; Pregnancy; Primates; Puberty; Radiation Induced DNA Damage; Research; Risk; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Staging; Stem cells; Testing; Time; Tissue Sample; Tumor Suppressor Genes; bisphenol A; cell growth; cell transformation; disorder prevention; in vitro Assay; innovation; interest; irradiation; malignant breast neoplasm; mammary gland development; mouse model; neoplastic; neoplastic cell; nonhuman primate; novel; polycarbonate plastic; self-renewal; stem cell niche; steroid hormone receptor; tumorigenesis; xenoestrogen

DESCRIPTION (provided by applicant): Exposure to environmental synthetic estrogens, such as bisphenol A (BPA), has been implicated to contribute to the increasing incidence of breast cancer. Bisphenol A is a most pervasive chemical in modern life as a component of polycarbonate plastics and epoxy resins used widely for food and beverage containers and dental sealants. Perinatal exposure to low, environmentally relevant doses of BPA in rodents resulted in induction of preneoplastic ductal hyperplasias, carcinoma in situ, and increased susceptibility to tumorigenesis. However, the underlying mechanism for these observations is unclear. The murine mammary stem cells (MaSCs) have the potential to drive mammary gland development during puberty, and growth and remodeling during pregnancy. Recent lineage tracing studies also indicated the presence of a hierarchy of stem cells in the murine mammary gland. Significantly, these distinct unipotent basal and luminal MaSCs have been matched with different subtypes of breast cancer by their specific gene-expression signatures. Furthermore, modulation of oncogenes and tumor suppressors has been shown to increase stem cell compartment and self-renewal function of MaSCs, suggesting that alteration of MaSC frequency and function may lead to transformation and tumorigenesis. Unpublished results indicate that low dose BPA exposure during puberty can alter the number of different lineage MaSCs. Recent animal studies showed that BPA also promoted tumor cell growth through estrogenic signaling implicating the risk of development and progression of mammary cancer by BPA exposure at various time points throughout the lifespan. Thus it is hypothesized that mammary gland exposed to BPA at a susceptible window may lead to its susceptibility to tumorigenesis through a MaSC and/or stem cell niche mediated mechanism. In addition to mice, the intent is to also use common marmoset to determine the effect of BPA on its MaSC function and transformation because nonhuman primates, with their close phylogenetic relationship to humans, can better simulate the effects of physiological and pathological factors on humans. This hypothesis will be tested with three specific aims. First, the effect of BPA will be determined on MaSC function of non-primate and primate subjects. A novel in vitro assay developed in this laboratory will be exploited, instead of cell surface markers that are not specific for MaSCs, to quantify the alteration of basal and luminal MaSC number after systemic BPA treatment in various developmental windows of the mammary gland of mice and marmoset. Second, a determination of the effect of low dose irradiation on the transformation potential of MaSCs derived from BPA-exposed mice will be accomplished. The hypothesis to be tested for this specific aim is that the transforming activity of BPA may be more evident in combination with a DNA damaging agent such as ionizing radiation, which is a known risk factor for breast cancer. Third, the effect of BPA treatment on MaSC function of obese mice and marmosets will be examined. This proposed research will not only answer the question of whether BPA- induced morphogenesis changes in different developmental windows of mammary gland has a stem cell origin, but also shed light on MaSC susceptibility to multiple risk factor-induced cell transformation such as xenoestrogens, irradiation, and obesity, which will have important implications in disease prevention for human breast cancer.

描述（由申请人提供）：暴露于环境合成雌激素（例如双酚A（BPA））已被牵涉到有助于增加乳腺癌发生率的增加。 双足A是现代生活中最普遍的化学物质，作为聚碳酸酯塑料和环氧树脂的组成部分，用于食品和饮料容器和牙科密封剂。 在啮齿动物中，围产期暴露于低剂量的BPA剂量，导致诱导癌性导管增生，原位癌和对肿瘤发生的易感性增加。 但是，这些观察结果的基本机制尚不清楚。鼠乳腺干细胞（MASC）有可能在青春期期间驱动乳腺发育，以及怀孕期间的生长和重塑。 最近的谱系追踪研究还表明，在鼠乳腺中存在干细胞的层次结构。 值得注意的是，这些独特的基础和腔腔女性通过其特定的基因表达特征与不同的乳腺癌亚型相匹配。 此外，已经证明对癌基因和肿瘤抑制剂的调节会增加MASC的干细胞室和自我更新功能，这表明MASC频率和功能的改变可能导致转化和肿瘤发生。未发表的结果表明，青春期期间的低剂量BPA暴露会改变不同的谱系MASC的数量。最近的动物研究表明，BPA还通过雌激素信号传导促进了肿瘤细胞的生长，这暗示着在整个寿命的各个时间点上通过BPA暴露的乳腺癌发展和进展的风险。 因此，假设在易感窗口暴露于BPA的乳腺可能会导致其通过MASC和/或干细胞小裂介导的机制对肿瘤发生的敏感性。除了小鼠外，其目的还应使用常见的摩尔马斯群岛来确定BPA对其MASC功能和转化的影响，因为非人类灵长类动物与人类有密切的系统发育关系可以更好地模拟生理和病理因素对人类的影响。该假设将以三个特定目的进行检验。首先， BPA的影响将确定对非成就和灵长类动物受试者的MASC功能。将利用在该实验室开发的一种新型体外测定法，而不是细胞表面标记 不是针对MASC的特定的，可以量化全身性BPA治疗后在小鼠和果泥的各种发育窗口中的基础和腔内MASC数的变化。其次，将确定低剂量辐射对源自BPA暴露小鼠的MASC的转化潜力的影响。要测试的这一特定目的的假设是，与DNA损伤剂（例如电离辐射）相结合，BPA的转化可能更为明显，这是乳腺癌的已知危险因素。第三，将检查BPA治疗对肥胖小鼠和果冻的MASC功能的影响。这项拟议的研究不仅将回答以下问题：乳腺不同发育窗口中BPA诱导的形态发生变化是否具有干细胞起源，而且还阐明了对多种风险因素诱导的细胞转化的MASC敏感性，例如内纳雌激素，辐照和肥胖，这对预防人类乳腺癌对疾病预防疾病对人类乳腺癌有重要影响。