DESCRIPTION (provided by applicant): Puberty and young adulthood are periods of high susceptibility to environmental and life style factors that increase breast cancer risk. We intend to identify how a high animal fat diet (HFD) consumed during puberty or young adulthood increases breast cancer risk. Ovarian hormones are implicated in the etiology of breast cancer. Estrogenic endocrine disrupting chemicals (EDCs) may act as agonists or antagonists during mammary gland development and mammary tumorigenesis, and should be studied to evaluate their potential in promoting breast cancer. We will study the interaction of HFD with a widely used but understudied EDC, oxybenzone (benzophenone-3, BP-3)--a common ingredient in sunscreen and other personal use products, to affect breast cancer risk. Using a transdisciplinary approach, findings in mice will be translated to humans to identify predictive biomarkers for risk and intervention strategies to reduce that risk. Recently, HFD was shown to increase premenopausal breast cancer risk in normal weight, but not overweight, young women. This agrees with our published and preliminary studies identifying both pubertal and adult windows of susceptibility (WOS) to the promotional effects of HFD in obesity-resistant BALB/c mice. Of note, HFD promoted basal-like breast cancer, which also predominantly occurs in young women. The pubertal WOS for HFD tumor promotion indicates potential efficacy of early age preventative intervention to reduce adult breast cancer risk. This project will: 1) Determine, under low fat diet (LFD) and HFD, BP-3 dosages in mice corresponding to human low spring/fall and high summer exposure urine levels, and then assess BP-3 effects on pubertal mammary gland development and adult morphology, body weight, and reproductive parameters relevant to the action of BP-3 as an EDC; 2) Determine BP-3 effects on mammary tumor susceptibility in two mouse breast cancer models (p53-null and TIP30-null transplant BALB/c mice) fed HFD vs. LFD, and identify pubertal vs. adult intermediate biomarkers, focusing on inflammatory and proliferative processes associated with tumorigenesis; 3) Test interventions against immune cells and growth factor pathways to alter intermediate biomarkers and ultimately reduce mammary tumorigenesis; 4) Analyze a human young adult female established cohort for the relationship(s) among intermediate serum biomarkers, HFD, BMI, and BP-3 exposure that may be predictive of increased premenopausal breast cancer risk; 5) Researchers will interact regularly with a Breast Cancer Advocate Advisory Board to receive input about the research directions, addressing concerns of affected communities. Research will be translated for education and risk reduction messages, disseminated in collaboration with MSU Extension, and message efficacy will be assessed by communication scientists. These studies will elucidate mechanisms linking HFD and an EDC with proliferative and immune biomarkers of breast cancer risk and identify strategies for early prevention and intervention to reduce breast cancer, particularly basal-like mammary cancer for which approaches to intervention are limited.

PUBLIC HEALTH RELEVANCE: This project employs a transdisciplinary approach using breast cancer animal models to test how combined exposure during puberty and young adulthood to a high animal fat diet in the absence of weight gain and a component of sunscreen (BP-3) with hormone-like effects that is also present in many personal care products promotes the development of basal-like breast cancers in young adult mice. We will identify intermediate biomarkers of increased breast cancer risk in mice, focusing on altered activity of growth factors and the immune system that will then be tested in a cohort of young women in relation to their exposure to BP-3, consumption of dietary fat, and normal weight versus overweight/obesity. It is anticipated that the results of this research will identify new targets for prevention and intervention against breast cancer, particularly basal-like breast cancer, for which there have been limited options for treatment.