The factors controlling rat pituitary hyperplasia and neoplastic development will be investigated. Analysis of the control of pituitary proliferation and prolactin gene expression by estrogen, basic fibroblast growth factor (bFGF), and specific hypothalamic hormones including growth hormone releasing hormone (GHRH) and gonadotropin releasing hormone (GnRH) will be investigated in vitro in defined serum-free media and in vivo. The regulatory role of the pituitary specific transcription factor Pit-1 on prolactin expression and on cell growth will be investigated in vitro directly and with anti-sense oligonucleotides. A new model of pituitary cell hyperplasia using GH3 cells transfected with the GHRH and GnRH genes will be developed to analyze the sequential development of hyperplasia and the possible progression to neoplasia in the rat pituitary. The role of the folliculo-stellate pituitary cells in pituitary tumor development will be investigated. These cells produce bFGF and S-100 protein. We have found that S-100 protein stimulates prolactin hormone secretion. Because folliculo-stellate cells are increased in hyperplastic pituitaries and are not present in transplantable pituitary tumors, these cells may play a critical role during tumor development. Analysis of enriched populations of folliculo-stellate cells by coculture experiments with normal and hyperplastic prolactin cells and with transplantable pituitary tumor cells will provide new information about the role of folliculo-stellate cells in tumor development. The effects of estrogen on prolactin gene methylation and on possible modification in the dopamine and estrogen receptor proteins during tumor development will also be investigated with our well-established models of pituitary hyperplasia. The long-term objections of this study are to analyze the mechanism by which estrogen, bFGF and specific hypothalamic hormones influence hyperplasia and neoplastic development in pituitary tissues in order to gain more information about the biology of pituitary cells. The data from these studies may lead to a better understanding of the development of pituitary neoplasms and may provide more effective means of treating these neoplasms.
