Mammary carcinogenesis: pubertal and adult effects of high fat diet+oxybenzone

 说明(申请人提供)：青春期和青春期是环境和生活方式因素增加乳腺癌风险的高度敏感时期。我们打算确定青春期或青春期食用高动物脂肪饮食(HFD)如何增加乳腺癌风险。卵巢激素与乳腺癌的病因有关。雌激素内分泌干扰物(EDCs)在乳腺发育和乳腺肿瘤发生过程中可能起到激动剂或拮抗剂的作用，应对其进行研究以评估其促进乳腺癌的潜力。我们将研究HFD与一种广泛使用但研究较少的EDC的相互作用，氧苯酮(二苯甲酮-3，BP-3)--防晒霜和其他个人使用产品中的常见成分，以影响乳腺癌风险。利用跨学科的方法，在小鼠身上的发现将被转化为人类，以确定风险的预测性生物标记物和降低风险的干预策略。最近，HFD被证明在正常体重但不是超重的年轻女性中会增加绝经前乳腺癌的风险。这与我们发表的初步研究一致，该研究确定了青春期和成人对HFD在肥胖抵抗BALB/c小鼠中的促进作用的易感窗口(WOS)。值得注意的是，HFD促进了基底样乳腺癌，这种癌症也主要发生在年轻女性中。青春期WOS对HFD肿瘤的促进作用表明早期预防性干预具有降低成人乳腺癌风险的潜在效果。本项目将：1)在低脂饮食(LFD)和高脂饮食(HFD)下，测定对应于人类春秋低暴露和夏季高暴露尿量的小鼠的BP-3剂量，然后评估BP-3对青春期乳腺发育和成人形态、体重以及与BP-3作为EDC作用相关的生殖参数的影响；2)在两种给予HFD和LFD的小鼠乳腺癌模型(p53基因缺失和TIP30基因缺失移植的BALB/c小鼠)中，确定BP-3对乳腺癌易感性的影响，并确定青春期和成人的中间生物标志物，重点关注与肿瘤发生相关的炎症和增殖过程；3)测试针对免疫细胞和生长因子途径的干预措施，以改变中间生物标记物，并最终降低乳腺肿瘤的发生；4)分析一组年轻成年女性患者的研究结果，以寻找可能预测绝经前乳腺癌风险增加的中间血清生物标志物、高脂血症、体重指数和BP-3暴露之间的关系(S)；5)研究人员将定期与乳腺癌倡导者顾问委员会进行互动，以听取有关研究方向的意见，解决受影响社区的担忧。研究将被翻译成教育和减少风险的信息，与密歇根州立大学的推广合作传播，信息的有效性将由传播学家评估。这些研究将阐明HFD和EDC与乳腺癌风险的增殖和免疫生物标记物之间的联系机制，并确定早期预防和干预策略，以减少乳腺癌，特别是干预方法有限的基底细胞样乳腺癌。

 DESCRIPTION (provided by applicant): Puberty and young adulthood are periods of high susceptibility to environmental and life style factors that increase breast cancer risk. We intend to identify how a high animal fat diet (HFD) consumed during puberty or young adulthood increases breast cancer risk. Ovarian hormones are implicated in the etiology of breast cancer. Estrogenic endocrine disrupting chemicals (EDCs) may act as agonists or antagonists during mammary gland development and mammary tumorigenesis, and should be studied to evaluate their potential in promoting breast cancer. We will study the interaction of HFD with a widely used but understudied EDC, oxybenzone (benzophenone-3, BP-3)--a common ingredient in sunscreen and other personal use products, to affect breast cancer risk. Using a transdisciplinary approach, findings in mice will be translated to humans to identify predictive biomarkers for risk and intervention strategies to reduce that risk. Recently, HFD was shown to increase premenopausal breast cancer risk in normal weight, but not overweight, young women. This agrees with our published and preliminary studies identifying both pubertal and adult windows of susceptibility (WOS) to the promotional effects of HFD in obesity-resistant BALB/c mice. Of note, HFD promoted basal-like breast cancer, which also predominantly occurs in young women. The pubertal WOS for HFD tumor promotion indicates potential efficacy of early age preventative intervention to reduce adult breast cancer risk. This project will: 1) Determine, under low fat diet (LFD) and HFD, BP-3 dosages in mice corresponding to human low spring/fall and high summer exposure urine levels, and then assess BP-3 effects on pubertal mammary gland development and adult morphology, body weight, and reproductive parameters relevant to the action of BP-3 as an EDC; 2) Determine BP-3 effects on mammary tumor susceptibility in two mouse breast cancer models (p53-null and TIP30-null transplant BALB/c mice) fed HFD vs. LFD, and identify pubertal vs. adult intermediate biomarkers, focusing on inflammatory and proliferative processes associated with tumorigenesis; 3) Test interventions against immune cells and growth factor pathways to alter intermediate biomarkers and ultimately reduce mammary tumorigenesis; 4) Analyze a human young adult female established cohort for the relationship(s) among intermediate serum biomarkers, HFD, BMI, and BP-3 exposure that may be predictive of increased premenopausal breast cancer risk; 5) Researchers will interact regularly with a Breast Cancer Advocate Advisory Board to receive input about the research directions, addressing concerns of affected communities. Research will be translated for education and risk reduction messages, disseminated in collaboration with MSU Extension, and message efficacy will be assessed by communication scientists. These studies will elucidate mechanisms linking HFD and an EDC with proliferative and immune biomarkers of breast cancer risk and identify strategies for early prevention and intervention to reduce breast cancer, particularly basal-like mammary cancer for which approaches to intervention are limited.