DESCRIPTION (provided by applicant): Numerous studies have shown associations between markers of fetal growth and important domains of adult health. In particular, several recent studies suggest that high birth weight may be associated with an increased risk of breast cancer later in life. The existing literature on birth weight and breast cancer risk, while intriguing, falls short by its inability to address the following: (1) potential confounding by family factors (e.g., socioeconomic status); (2) the importance of and possible interaction with other measures of fetal growth; (3) the independent effect of maternal characteristics and exposures; (4) potential biological mechanisms; (5) the contribution of postnatal growth; and (6) mediation by adult risk factors. We will address these limitations by use of a novel study design examining the association of early life factors with mammographic density, a strong predictor of future breast cancer risk. Specifically, we will recruit a sibling sample of 325 female pairs (n=650) and a single child sample of 350 high birth-weight (>=4000g) females for a total of 1000 subjects. All females are offspring of pregnant women enrolled during 1959 to 1967 in two New England sites (Boston and Providence) of the National Collaborative Perinatal Project (NCPP) and in the Childhood Health and Development Study (CHDS). The sibling design will allow us to control for family effects such as socioeconomic status that may influence both birth-weight and adult risk factor patterns. Exposure information will be derived from prospectively collected pro and postnatal data on mothers, infants, and childhood growth. Maternal sera collected during the third trimester will be used to measure estrogen (El, E2, E3), and testosterone. Along with the mammogram, we will also collect adult risk factor data through interview and laboratory assays (including measures of IGF-I, IGFBP-3). We hypothesize that high birth weight, high placental weight, high placental/birth weight ratio, high maternal pregnancy weight gain, and high maternal estrogen levels will increase mammographic density in the daughters, and that maternal preeclampsia and higher levels of maternal testosterone will decrease mammographic density in the daughters. We will further examine whether any of these associations are mediated by childhood growth patterns and adult risk factors. This study will advance the literature on early determinants of breast cancer risk by directly addressing many of the limitations in the existing literature, allowing a more thorough inspection into what may shape early breast cancer susceptibility.