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

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，特别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。乳腺癌的人类和动物研究表明，炎症过程（IP）有助于肿瘤的增殖和转移。BALB/c小鼠的初步结果显示，青春期暴露于高脂肪饮食（HFD）会增加青春期乳腺增生和dba诱导的乳腺肿瘤发生。研究者还将证明青春期接触HFD会诱发IP。重要的是，这些影响发生在没有肥胖的情况下。他们假设HFD通过诱导IP增加乳腺增生和乳腺肿瘤发生。IP是乳腺正常发育的重要组成部分。研究人员最近发现了一种新的途径，将黄体酮(P)与乳腺发育过程中IP的调节联系起来。他们进一步假设，p诱导的RANKL在乳腺上皮中的表达是通过激活NFkB（促炎基因产物的转录调节因子）来促进正常IP的关键，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了乳腺的增殖和肿瘤发生。他们将在BALB/c小鼠的正常青春期乳腺发育过程中，以及喂食对照和HFD的小鼠的DMBA和p53-/-癌变过程中测试这些假设。研究人员还将测试几种实验性干预策略，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和癌变过程中的调节作用，可以为其他环境因素（即内分泌干扰物、毒物）如何增加乳腺癌易感性提供相关信息。研究人员将与他们的社区乳腺癌倡导伙伴密歇根乳腺癌联盟一起，将他们的研究结果翻译并传达给有关公众。

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.