Estrogen has been implicated in the control of pituitary tumor induction and growth in rats; the majority of these tumors involve prolactin (PRL)- secreting lactotropes. The incidence of PRL-secreting pituitary tumors (prolactinomas) is high in human patients, and increased tumor growth under estrogenic influence in female patients is often of clinical concern. The goal of this proposal is to determine the role of transforming growth factor-beta1 (TGF-beta1) in the estrogen-regulated lactotropic (PRL- secreting cells) secretion and growth, using the rat as an animal model. The hypotheses to be tested are i) that TGF-beta1 inhibits lactotropic secretion and proliferation by an autocrine/paracrine mechanism and ii) that inhibition of pituitary TGF-beta1 activity is one of the mechanisms by which estrogen induces neoplasm in the lactotrope.
specific aims are to: 1) determine the action of TGF-beta1 in estrogen-regulated PRL secretion, PRL mRNA expression and lactotropic proliferation; 2) elucidate estrogen effects on TGF-beta1 protein production and secretion; 3) evaluate estrogen action on TGF-beta1 mRNA expressions in the pituitary; 4) understand the interaction between estrogen, TGF-beta1 and PRL at the level of gene transcription. Several technological approaches will be utilized to achieve these aims. These will include: a) cell cultures of normal and tumor pituitaries; b) the identification of TGF-beta1 producing cells in the pituitary gland by using immunohistochemistry and in situ hybridization procedures; c) the measurement of TGF-beta1 and PRL secretion in the pituitary by specific radioimmunoassays; d) the determination of pituitary cell proliferation by using a bromodeoxyuridine incorporation assay, e) the assay of TGF-beta1 and PRL mRNA levels using northern blot and in situ hybridization techniques, f) the study of the interaction between TGF- beta1, estrogen and PRL at the gene level by nuclear run on transcription and mRNA stability assays. The proposed research will yield an increased understanding of the mechanisms involved in estrogen-induced abnormalities in the function and growth of lactotropes. Such understanding should provide new clues to the process involved in the formation of prolactinomas.
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