Perinatal exposure to estradiol results in permanent alterations in mammary development and an increased frequency of mammary dysplasia and tumors. We have demonstrated an enhanced in vitro sensitivity to hormones of mammary tissue following perinatal estradiol treatment, and determined that casein gene expression is a specific marker of mammary differentiation. The objective of this proposal is to define the relation of perinatal hormone treatment, and the carcinogen, DMBA, on the regulation of mammary development and gene expression. The interaction of perinatal estrogen treatment with the response to DMBA exposure will be correlated with the normal hormonal regulation of casein and prolactin receptor gene expression. These studies are designed to test the hypothesis that perinatal hormone exposure results in an increased susceptibility of mammary tissue to agents known to initiate transformation, with the possibility of a corresponding loss in hormonally regulated differentiated function. The effects of perinatal treatment will be compared in BALB/c mouse mammary glands. Induction of both casein and prolactin receptors will be compared with morphology using fluorescent antibody and peroxidase staining technics to detect these specific proteins (a lactogenic hormone combination: prolactin, insulin and hydrocortison, will be used in culture under defined conditions to determine the effects of perinatal steroid exposure at the cell level. The response to hormone will also be tested following carcinogen administration Cell level effects will be confirmed by use of in situ hybridization. Transformation will be ascertained by transplant of suspect cells to nude mice. The proposed experiments may help to clarify the complex interrelation of hormones and carcinogens with mammary tissue, at the cell level, especially during the early phases or stages of the neoplastic transformation, and allow identification of stages at which intervention with the process may be possible.
