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

 描述（由申请人提供）：青春期和青年期是对增加乳腺癌风险的环境和生活方式因素高度敏感的时期。我们打算确定在青春期或成年早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。雌激素性内分泌干扰物（EDCs）在乳腺发育和乳腺肿瘤发生过程中可能起激动剂或拮抗剂的作用，应对其进行研究以评估其促乳腺癌的潜力。我们将研究HFD与广泛使用但研究不足的EDC，羟苯甲酮（二苯甲酮-3，BP-3）的相互作用-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。使用跨学科的方法，小鼠的研究结果将被转化为人类，以确定风险的预测生物标志物和降低风险的干预策略。最近，HFD被证明会增加正常体重的年轻女性绝经前乳腺癌的风险，但不会增加超重的风险。这与我们发表的初步研究一致，这些研究确定了青春期和成年期对HFD在肥胖抵抗BALB/c小鼠中的促进作用的敏感性窗口（WOS）。值得注意的是，HFD促进了基底样乳腺癌，这也主要发生在年轻女性中。HFD肿瘤促进的青春期WOS表明早期预防性干预对降低成人乳腺癌风险的潜在有效性。该项目将：1）在低脂饮食（LFD）和HFD下，确定小鼠中对应于人低春/秋和高夏季暴露尿水平的BP-3剂量，然后评估BP-3对青春期乳腺发育和成年形态、体重和与BP-3作为EDC的作用相关的生殖参数的影响; 2）在两种小鼠乳腺癌模型中确定BP-3对乳腺肿瘤易感性的影响（p53-无效和TIP 30-无效移植BALB/c小鼠）喂食HFD与LFD，并鉴定青春期与成年期中间生物标志物，3）测试针对免疫细胞和生长因子途径的干预措施，以改变中间生物标志物并最终减少乳腺肿瘤发生; 4）分析人类年轻成年女性建立的群组的中间血清生物标志物、HFD、BMI、和BP-3暴露，这可能是预测增加绝经前乳腺癌的风险; 5）研究人员将定期与乳腺癌倡导咨询委员会互动，以接收有关研究方向的输入，解决受影响社区的关注。将把研究成果转化为教育和减少风险的信息，与密歇根州立大学推广部合作传播这些信息，传播科学家将评估信息的效力。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志物之间的联系机制，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.