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.
