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

乳腺癌的发生：高脂肪饮食羟苯酮对青春期和成人的影响

• 批准号: 8999647
• 负责人: SANDRA Z HASLAM
• 金额: $ 88.97万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999647
• 关键词: Address; Adult; Advocate; Affect; Age; Agonist; Agreement; Animal Model; Animals; Benzophenones; Biological Markers; Body Weight; Breast Cancer Education; Breast Cancer Model; Breast Carcinoma; Chemicals; Collaborations; Communication; Communities; Consumption; Development; Diet; Dietary Fats; Education; Effectiveness; Endocrine Disruptors; Etiology; Exposure to; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Goals; Growth Factor; HTATIP2 gene; Hormones; Human; Immune; Immune system; Inbred BALB C Mice; Incidence; Inflammatory; Intervention; Life; Life Style; Link; Mammary Neoplasms; Mammary Tumorigenesis; Methods; Modeling; Morphology; Mus; Obesity; Ovarian hormone; Overweight; Pathway interactions; Population; Predisposition; Premenopause; Prevention strategy; Preventive Intervention; Process; Puberty; Publishing; Research; Research Personnel; Resistance; Risk; Risk Reduction; Rural; Science; Scientist; Self Care; Serum; Signal Transduction; Staging; Stimulus; Sunscreening Agents; Testing; Translating; Translations; Transplantation; Treatment Efficacy; Tumor Promotion; Update; Urine; Weight; Weight Gain; Woman; anticancer research; base; cancer risk; cell growth; cohort; dosage; efficacy testing; evidence base; falls; feeding; health literacy; immune function; malignant breast neoplasm; mammary gland development; meetings; member; novel strategies; programs; public health relevance; reproductive; theories; tumor; tumorigenesis; young adult; young woman

 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.

 描述（由适用提供）：青春期和年轻的成年期是增加乳腺癌风险的环境和生活方式因素的高敏感性。我们打算确定在青春期或成年期间消耗的高动物脂肪饮食（HFD）如何增加乳腺癌的风险。乳腺癌病因中隐含卵巢激素。雌激素内分泌破坏化学物质（EDC）可以在乳腺发育和乳腺肿瘤发生过程中充当激动剂或拮抗剂，并应研究以评估其在促进乳腺癌方面的潜力。我们将研究HFD与广泛使用但已理解的EDC，氧气区（苯甲酮-3，BP-3）的相互作用，这是防晒霜和其他个人使用产品中的一种常见成分，以影响乳腺癌的风险。使用跨学科的方法，小鼠的发现将转化为人类，以识别风险和干预策略的预测生物标志物，以降低这种风险。最近，HFD被证明会增加日期前乳腺癌的正常体重风险，但不超重，年轻女性。这与我们已发表的初步研究一致，该研究确定了对HFD在抗肥胖症的BALB/C小鼠中的促进影响的青春期和成人易感性（WOS）。值得注意的是，HFD促进了基本的乳腺癌，这也主要发生在年轻女性中。 HFD肿瘤促进的青春期WO表明，早期预防性干预措施的潜在有效性以降低成人乳腺癌的风险。该项目将：1）在低脂肪饮食（LFD）和HFD下，在与人类低春季/秋季和夏季高暴露尿液水平相对应的小鼠中确定BP-3剂量，然后评估BP-3对与BP-3 As Edc的动作相关的青春期乳腺发育，体重和生殖参数相关的青春期乳腺发育，体重和生殖参数的影响； 2）确定BP-3对HFD与LFD的两种小鼠乳腺癌模型（p53-Null和Tip30-Null移植BALB/C小鼠）中对乳腺肿瘤易感性的影响，并鉴定出针对成人中间的生物标记物，重点是炎症性和繁殖过程，并与肿瘤发生相关； 3）针对免疫细胞和生长因子途径的测试干预措施改变中间生物标志物并最终减少乳腺肿瘤发生； 4）分析一个人类的年轻女性在中间血清生物标志物，HFD，BMI和BP-3暴露之间建立了对关系的队列，这可能预测了麻醉前乳腺癌的风险增加； 5）研究人员将定期与乳腺癌倡导者咨询委员会进行互动，以收到有关研究方向的意见，以解决受影响社区的关注。研究将被翻译以进行教育和降低风险信息，与MSU扩展合作传播，并且信息效率将由传播科学家评估。这些研究将阐明将HFD和EDC与乳腺癌风险的增殖和免疫生物标志物联系起来的机制，并确定早期预防和干预以减少乳腺癌的策略，尤其是基本的乳腺癌，而干预方法有限。