Impact of environmental metal/metalloid exposures on mammographic breast density, a marker of breast cancer

 描述（由申请人提供）：华盛顿医疗服务不足地区的居民表示担心，他们社区的癌症高发病率是由于他们的食物和水中的污染物，包括金属。我们实验室和其他实验室的结果表明，环境相关量的特定金属和类金属（称为金属雌激素）通过与受体的配体结合结构域（LBD）的高亲和力相互作用在体外和体内激活雌激素受体α（ERα）。这些金属和准金属分为两个独立的亚类，二价阳离子和含氧阴离子。我们实验室的新结果表明，金属雌激素也激活孕激素受体-B（PR-B）。激活ERα和潜在的PR-B的能力表明，环境暴露于具有雌激素和孕激素样活性的金属和类金属可能会增加患乳腺癌的风险。为回应社会人士的关注，本申请将通过检验以下假设来解决暴露于金属和类金属是否会增加患乳腺癌的风险的问题：类似的活动与绝经过渡期妇女较高的乳房X线摄影密度有关，并延迟或减少乳腺的退化，在此期间，乳房X线摄影的乳腺密度下降。目的1将确定金属和类金属是否模拟雌激素和孕激素对绝经动物模型中乳腺形态、干细胞和祖细胞以及基因表达的影响（目的1a），并确定金属和类金属在体外试验中激活PR-B的机制（目的1b）。目的2将确定环境暴露于金属激素是否与绝经过渡期乳腺密度的变化有关，并确定金属和类金属改变乳腺密度的机制。具体而言，目标2将确定：a，较高的金属激素水平是否与乳腺摄影密度增加相关; B，较高的金属激素水平是否与绝经过渡期维持较高的乳腺密度相关; c，钙通路的多态性是否与乳腺摄影密度增加相关，表明二价阳离子金属激素增加风险的机制。为了实现这些目标，我们将继续与我们的合作伙伴接触，以获得他们的投入，帮助收集数据，并将科学发现翻译和传达给社区。

 DESCRIPTION (provided by applicant):Residents in medically underserved areas of Washington, DC have express the concern that the high incidence of cancer in their community is due to contaminants in their food and water, including metals. Results from our laboratory and others show that environmentally relevant amounts of specific metals and metalloids, referred to as metalloestrogens, activate estrogen receptor-alpha (ERα) in vitro and in vivo through a high affinity interaction with the ligand binding domain (LBD) of the receptor. These metals and metalloids fall into two separate subclasses, bivalent cations and oxyanions. New results from our laboratory suggest that metalloestrogens also activate progesterone receptor-B (PR-B). The ability to activate ERα, and potentially PR-B suggests that environmental exposure to metals and metalloids with estrogen- and progestin-like activity may increase the risk of developing breast cancer. In response to the concerns of the community, this application will address the question whether exposure to metals and metalloids increases the risk of developing breast cancer by testing the hypothesis that higher lifetime environmental exposure to metals and metalloids with estrogen- and progesterone-like activity is associated with higher mammographic density in women during the menopausal transition and delays or reduces the involution of mammary gland and the decline in mammographic breast density during this period. Aim 1 will determine whether metals and metalloids mimic the effects of estrogens and progestin on mammary gland morphology, stem and progenitor cells, and gene expression in a menopausal animal model (Aim 1a) and define the mechanisms by which metals and metalloids activate PR-B in in vitro assays (Aim 1b). Aim 2 will determine whether environmental exposure to metallohormones is associated with changes in breast density through the menopausal transition and define the mechanism by which metals and metalloids alter breast density. Specifically, Aim 2 will establish if: a, higher metallohormone levels are associated with increased mammographic density; b, higher metallohormone levels are associated with maintenance of higher breast density through the menopausal transition; and c, polymorphisms in the calcium pathway are associated with increased mammographic breast density indicating the mechanism through which bivalent cationic metallohormones increase risk. To accomplish these aims, we will continue to engage with our partners to get their input, to help collect data, and to translate and communicate the scientific findings to the community.