Pubertal high fat diet: effects on inflammation, mammary development and cancer

青春期高脂肪饮食：对炎症、乳房发育和癌症的影响

• 批准号: 8463533
• 负责人: SANDRA Z HASLAM
• 金额: $ 44.24万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463533
• 关键词: Address; Adult; Advocate; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biological Models; Breast; Cancer Advocacy; Cells; Collaborations; Communication; Communities; Development; Diet; Dietary Intervention; Effectiveness; Endocrine Disruptors; Environmental Exposure; Environmental Risk Factor; Epithelial; Estrogens; Exposure to; Fatty acid glycerol esters; Gene Proteins; Hormonal; Hormones; Human; Immune; Inbred BALB C Mice; Infiltration; Inflammation; Inflammatory; Information Dissemination; Intervention; Knockout Mice; Leukocytes; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Michigan; Mus; Neoplasm Metastasis; Obesity; Pathway interactions; Pharmaceutical Preparations; Population; Predisposition; Principal Investigator; Process; Progesterone; Proteins; Puberty; Regulation; Research; Research Personnel; Research Project Grants; Role; Specialist; TNFSF11 gene; Testing; Time; Translating; Transplantation; Update; carcinogenesis; dimethylbenzanthracene; efficacy testing; eosinophil; feeding; in vivo; inhibitor/antagonist; interest; macrophage; malignant breast neoplasm; mammary epithelium; mammary gland development; mast cell; meetings; novel; pubertal timing; toxicant; tumor; tumorigenesis; web site

DESCRIPTION (provided by applicant): Studies in humans and animals indicate that the origins of breast cancer likely occur early in development, especially during puberty, a time of rapid breast development. Animal studies show that pubertal diet and environmental exposures can increase mammary cancer susceptibility. Human and animal studies of breast cancer show inflammatory processes (IP) contribute to tumor proliferation and metastasis. Preliminary results in BALB/c mice show pubertal exposure to a high fat diet (HFD) increases pubertal mammary gland proliferation and DMBA-induced mammary tumorigenesis. The investigators will also show that pubertal exposure to HFD induces IP. Importantly, these effects occur without obesity. They hypothesize that HFD increases mammary gland proliferation and mammary tumorigenesis through induction of IP. IP are a necessary and key component of normal mammary gland development. The investigators recently identified a novel pathway linking progesterone (P) to regulation of IP during mammary gland development. They further hypothesize that P-induced RANKL expression in the mammary epithelium is critical in promoting normal IP by activating NFkB, a transcriptional regulator of proinflammatory gene products, and that RANKL is the central regulator of HFD-induced IP in the mammary gland. The investigators propose that the observed HFD-induced RANKL expression, subsequent IP activation through NFkB, and peri-epithelial infiltration of macrophages and eosinophils promote both mammary gland proliferation and tumorigenesis. They will test these hypotheses during normal pubertal mammary gland development, and during DMBA and p53-/- carcinogenesis in BALB/c mice fed control and HFD. The investigators will also test several experimental intervention strategies to overcome the negative effects of diet on inflammation, and on mammary cancer development. Understanding the regulation of IP in normal pubertal mammary gland development, as well as in carcinogenesis, may provide relevant information about how other environmental factors (i.e., endocrine disrupters, toxicants) may increase susceptibility to mammary cancer. With their community breast cancer advocacy partner, Michigan Breast Cancer Coalition, the investigators will translate and communicate their research findings to the concerned public.

描述（由申请人提供）：在人类和动物中进行的研究表明，乳腺癌的起源可能发生在发育早期，特别是在青春期，这是乳房快速发育的时期。动物研究表明，青春期饮食和环境暴露可增加乳腺癌的易感性。乳腺癌的人类和动物研究表明，炎症过程（IP）有助于肿瘤增殖和转移。BALB/c小鼠的初步结果显示，青春期暴露于高脂饮食（HFD）会增加青春期乳腺增生和DMBA诱导的乳腺肿瘤发生。 研究者还将证明青春期暴露于HFD可诱导IP。 重要的是，这些影响不会发生肥胖。 他们假设HFD通过诱导IP增加乳腺增生和乳腺肿瘤发生。IP是正常乳腺发育的必要和关键成分。 研究人员最近发现了一种新的途径，将孕酮（P）与乳腺发育过程中的IP调节联系起来。 他们进一步假设，P诱导的乳腺上皮中RANKL表达在通过激活NFkB（促炎基因产物的转录调节因子）促进正常IP中至关重要，并且RANKL是乳腺中HFD诱导的IP的中心调节因子。 研究者提出，观察到的HFD诱导的RANKL表达、随后通过NFkB的IP活化以及巨噬细胞和嗜酸性粒细胞的上皮周浸润促进乳腺增殖和肿瘤发生。 他们将在正常青春期乳腺发育期间以及在喂食对照和HFD的BALB/c小鼠中DMBA和p53-/-致癌期间测试这些假设。 研究人员还将测试几种实验干预策略，以克服饮食对炎症和乳腺癌发展的负面影响。 了解IP在正常青春期乳腺发育以及癌变过程中的调节，可以提供有关其他环境因素（即，内分泌干扰物、有毒物质）可能会增加乳腺癌的易感性。 与他们的社区乳腺癌宣传合作伙伴密歇根州乳腺癌联盟，研究人员将翻译和沟通他们的研究结果，以有关公众。