ETIOLOGY OF ESTROGEN INDUCED PROLACTIN TUMORS

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Development of estradiol: (E2) induced prolactinomas involves cell division of lactotrophs, morphological changes in folliculi- stellate cells (FSC) and development of a direct arterial blood supply. We hypothesize that these changes are caused by direct actions of E2 at various target sites as well as the indirect actions of E2 to inhibit hypothalamic dopaminergic (DA) regulation. We will test this hypothesis in two strains of rats, Fisher 344 rats that are extremely sensitive to the tumorogenic action of E2 and Sprague-Dawley rats that are relatively insensitive. E2 will be administered alone or in combination with the DA antagonist trifluoperazine or agonist bromoergocryptine (CB154). FSC contain large amounts of basic fibroblast growth factor (bFGF) and show dramatic morphological changes following treatment of Fisher 344 rats with E2. We will determine whether during tumor formation there is an increase in bFGF production by measuring bFGF content by RIA and mRNA by northern blot hybridization or bFGF activity by measuring the number and affinity of FGF receptors. The site of bFGF production will be determined by immunocytochemistry. We will determine if FCS also produces large amounts of the proteolytic enzymes, plasminogen activator and type IV collagenase during tumor formation. These enzymes are an important component of tissue remodeling necessary for tumor growth and possibly a mechanism for the release of bFGF sequestered in basement membrane. Thirdly, we will determine if the expression of proto-oncogenes related to key regulatory processes in the AP is increased during various stages of tumor formation. mRNA levels will be determined for int-2 and hst which have considerable homology with FGF as well as erb-B, sis, Ha-ras, N-ras, Ki-ras, fos and myc. Cellular sites of oncogene expression will be determined by immunocytochemistry. Lastly, we have recently shown that the 16K fragment of prolactin (PRL) inhibits growth of endothelial cells. We will determine if 16K PRL production and receptors change during tumor formation. We will also test whether 16K PRL can inhibit growth of E2 produced prolactinomas in Fisher 344 rats, GH3 tumors in Wistar Furth rats and 7315a tumors in female Buffalo rats. These studies will increase our understanding of the mechanisms and cellular sites of action of E2 in tumor formation. Studies with 16K PRL could lead to the development of a new class of angiolytic drugs for treatment of cancer.