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

基本信息

批准号：
8136539
负责人：
SANDRA Z HASLAM
金额：
$ 45.14万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8136539
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

项目摘要

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）：对人类和动物的研究表明，乳腺癌的起源可能是在发育早期发生的，尤其是在青春期，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会增加乳腺癌的敏感性。人类和动物的乳腺癌研究表明炎症过程（IP）有助于肿瘤增殖和转移。 BALB/C小鼠的初步结果表明，青春期暴露于高脂饮食（HFD）会增加青春期乳腺增殖和DMBA诱导的乳腺肿瘤发生。研究人员还将表明，青春期暴露于HFD会引起IP。重要的是，这些影响没有肥胖。他们假设HFD通过诱导IP增加了乳腺增殖和乳腺肿瘤发生。 IP是正常乳腺发育的必要和关键组成部分。研究人员最近确定了一条新的途径，将孕酮（P）与乳腺发育过程中IP的调节联系起来。他们进一步假设乳腺上皮中P诱导的RANKL表达对于通过激活NFKB（促促促炎性基因产物的转录调节剂）来促进正常IP至关重要，而RANKL是HFD诱导的乳腺中IP的中心调节剂。研究人员建议观察到的HFD诱导的RANKL表达，随后通过NFKB激活以及巨噬细胞的上皮周围浸润和嗜酸性粒细胞促进乳腺增殖和肿瘤发生。他们将在正常的青春期乳腺发育期间以及在喂养控制和HFD的BALB/C小鼠中检验这些假设，以及在DMBA和p53 - / - 癌变期间。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育的负面影响。了解正常的青春期乳腺发育中IP的调节以及癌变中，可能会提供有关其他环境因素（即内分泌厌食症，毒物）如何增加对乳腺癌易感性的相关信息。与他们的社区乳腺癌倡导合作伙伴密歇根州乳腺癌联盟，研究人员将向有关公众转化并将其研究结果传达。