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: 8535764
• 负责人: LUZHE SUN
• 金额: $ 32.96万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535764
• 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; Right-On; Risk; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Simulate; 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)，已被认为会导致乳腺癌发病率增加。 双酚 A 是现代生活中最普遍的化学物质，是广泛用于食品和饮料容器以及牙科密封剂的聚碳酸酯塑料和环氧树脂的成分。 啮齿类动物在围产期接触低剂量、环境相关剂量的 BPA 会导致癌前导管增生、原位癌以及肿瘤发生的易感性增加。 然而，这些观察结果的潜在机制尚不清楚。小鼠乳腺干细胞 (MaSC) 有潜力驱动青春期乳腺发育以及怀孕期间乳腺生长和重塑。 最近的谱系追踪研究还表明，小鼠乳腺中存在干细胞层次结构。 值得注意的是，这些独特的单能基底和管腔 MaSC 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，癌基因和肿瘤抑制因子的调节已被证明可以增加干细胞区室和MaSC的自我更新功能，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，青春期接触低剂量的 BPA 可以改变不同谱系 MaSC 的数量。最近的动物研究表明，BPA 还通过雌激素信号促进肿瘤细胞生长，这表明在整个生命周期的不同时间点接触 BPA 会增加乳腺癌发生和进展的风险。 因此，假设乳腺在易感窗口暴露于 BPA 可能通过 MaSC 和/或干细胞生态位介导的机制导致其对肿瘤发生的易感性。除小鼠外，目的还在于利用普通狨猴来确定BPA对其MaSC功能和转化的影响，因为非人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。该假设将通过三个具体目标进行检验。首先， BPA 的影响将取决于非灵长类动物和灵长类动物受试者的 MaSC 功能。将利用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物 不是针对 MaSC 的特异性，用于量化小鼠和狨猴乳腺的各个发育窗口中全身 BPA 处理后基础和腔内 MaSC 数量的变化。其次，将确定低剂量照射对 BPA 暴露小鼠来源的 MaSC 转化潜力的影响。为实现这一特定目标而要测试的假设是，BPA 的转化活性在与 DNA 损伤剂（例如电离辐射）结合使用时可能会更加明显，电离辐射是乳腺癌的已知危险因素。第三，将检查 BPA 治疗对肥胖小鼠和狨猴 MaSC 功能的影响。这项研究不仅将回答BPA诱导的乳腺不同发育窗口的形态发生变化是否具有干细胞起源的问题，还将揭示MaSC对异雌激素、辐射和肥胖等多种危险因素诱导的细胞转化的易感性，这将对人类乳腺癌的疾病预防具有重要意义。