Elucidation of the molecular mechanisms underlying normal estrogen- induced growth of the reproductive tract is a key step in understanding the aberrant growth, differentiation, and carcinogenesis that results following developmental of persistent exposure to estrogen in rodents and humans. We have utilized a mouse model to provide a paradigm for obtaining a more comprehensive understanding of the role of peptide growth factors in steroid hormone action in the reproductive tract of women. Using immunohistochemistry, in situ and Northern RNA analyses of growth factor expression in the mouse reproductive tract, we provide evidence that estrogen induces a complex array of peptide growth factors such as TGF-betas, PDGFs, IGF1, lactoferrin, TGF-alpha and EGF,similar to those involved in wound healing, which is linked to the initiation of synchronized growth. Two of these estrogen-regulated genes, lactoferrin and EGF, are constitutive activated upon developmental exposure to estrogen. This permanent """"""""imprinting"""""""" of an estrogenized phenotype (epigenetic changes) most likely is instrumental in the establishment of the reproductive tract lesions. Tumor studies using female transgenic mice containing the human TGF-alpha gene (in collaboration with Dr. G. Merlino, NCI) reveal that persistent expression of this peptide increases the susceptibility of the reproductive tract to the development of proliferative and differentiation lesions. Our evidence suggests that estrogen utilizes components of the inflammatory pathway to bring about normal physiological growth and that inappropriate induction of components of this pathway contributes to disease. Studies of cultured uterine cells reveal that the in vitro environment results constitutive expression of genes that are under strict estrogen regulation in vivo. This suggests that the environment plays a central role in controlling steroid hormone response, and simple culture initiates the loss of hormone dependence. Because many fundamental questions remain concerning the roles of growth factors, receptors and other cytokines, our plans are to identify more human and mouse genes that characterize the different physiological states of normal and neoplastic tissue. The identification of multifunctional regulatory proteins in the reproductive tract significantly enhances our ability to interpret estrogen action and to provide potential biomarkers to evaluate disease states, which in turn may lead to the design of new agonists, antagonists, and neutralizing agents of potential therapeutic use.
