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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：
8664846
负责人：
SANDRA Z HASLAM
金额：
$ 44.69万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664846
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，乳腺癌的起源可能发生在发育早期，尤其是在乳房快速发育的青春期。动物研究表明，青春期饮食和环境暴露会增加乳腺癌的易感性。人类和动物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，青春期暴露于高脂肪饮食 (HFD) 会增加青春期乳腺增殖和 DMBA 诱导的乳腺肿瘤发生。研究人员还将证明，青春期接触 HFD 会诱发 IP。重要的是，这些影响在没有肥胖的情况下也会发生。他们假设 HFD 通过诱导 IP 增加乳腺增殖和乳腺肿瘤发生。 IP 是正常乳腺发育的必要且关键的组成部分。研究人员最近发现了一种将孕酮 (P) 与乳腺发育过程中 IP 调节联系起来的新途径。他们进一步假设 P 诱导的乳腺上皮中的 RANKL 表达对于通过激活 NFkB（促炎基因产物的转录调节因子）促进正常 IP 至关重要，并且 RANKL 是 HFD 诱导的乳腺 IP 的中心调节因子。研究人员提出，观察到的 HFD 诱导的 RANKL 表达、随后通过 NFkB 激活 IP 以及巨噬细胞和嗜酸性粒细胞的上皮周围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过程中以及在喂养对照和 HFD 的 BALB/c 小鼠的 DMBA 和 p53-/- 致癌过程中测试这些假设。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发生中的调节作用，可以提供有关其他环境因素（即内分泌干扰物、毒物）如何增加乳腺癌易感性的相关信息。研究人员将与社区乳腺癌倡导合作伙伴密歇根乳腺癌联盟合作，将他们的研究结果翻译并传达给相关公众。