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

描述（由申请人提供）：暴露于环境合成雌激素，如双酚A (BPA)，已被认为与乳腺癌发病率增加有关。双酚A是现代生活中最普遍的化学物质，是聚碳酸酯塑料和环氧树脂的一种成分，广泛用于食品和饮料容器以及牙科密封剂。围产期暴露于与环境相关的低剂量双酚a会导致啮齿动物肿瘤前导管增生、原位癌和肿瘤发生易感性增加。然而，这些观察的潜在机制尚不清楚。小鼠乳腺干细胞（MaSCs）具有在青春期和怀孕期间驱动乳腺发育和生长重塑的潜力。最近的谱系追踪研究也表明，在小鼠乳腺中存在一个干细胞层次结构。值得注意的是，这些独特的单能基底和腔内MaSCs通过其特定的基因表达特征与不同亚型的乳腺癌相匹配。此外，癌基因和肿瘤抑制因子的调节已被证明可以增加MaSC的干细胞室室和自我更新功能，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，青春期低剂量BPA暴露可以改变不同谱系MaSCs的数量。最近的动物研究表明，双酚a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暴露于双酚a会增加乳腺癌的发生和进展风险。因此，我们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易感肿瘤发生。除小鼠外，还打算利用普通狨猴来确定BPA对其MaSC功能和转化的影响，因为与人类有着密切的系统发育关系的非人灵长类动物可以更好地模拟生理和病理因素对人类的影响。这一假设将通过三个具体目标进行检验。首先,

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 Unpublished results indicate that low dose BPA exposure during puberty can alter the number of different lineage MaSCs.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.