THE ESTROGEN-RECEPTOR MODULATES GROWTH OF PITUITARY-TUMOR CELLS IN THE ABSENCE OF EXOGENOUS ESTROGEN

The GH(3) pituitary cell line has been used to investigate the role of the oestrogen receptor (ER) as a modulator of mitogenic signals in tu mour cells in the absence of exogenous oestrogen. Using a chemically d efined, serum- and oestrogen-free medium, we have demonstrated that st eroidal anti-oestrogens ICI 182780 164384 are capable of blocking grow th by more than 50% after 5 days of culture. Studies with conditioned medium have indicated that the basal growth is due to the secretion of autocrine growth stimulatory substances. Under serum- and oestrogen-f ree conditions, insulin and IGF-I increased the growth rate of these c ells by twofold over a 5-day treatment period, and this effect was als o blocked by the anti-oestrogens ICI 182780 and ICI 164384 (50% of max imum inhibition at 0.6 and 6 nM respectively). To explore the potentia l mechanism by which the ER apparently facilitates the growth factor e ffects under oestrogen-free conditions, GH(3) cells were transiently t ransfected with a plasmid reporter containing the vitellogenin oestrog en response element (Delta MTV-ERE-LUC). We have shown that as well as oestradiol (OE(2)), insulin and IGF-I induce luciferase activity by b etween two- and sevenfold (four experiments), and these effects were c ompletely blocked by ICI 182780. In contrast, growth factors and OE(2) were unable to induce luciferase expression when transfections were p erformed with a plasmid reporter lacking the oestrogen response elemen t. The studies presented here strongly suggest that, in the absence of oestrogen, the ER in these pituitary tumour cells has a role in growt h, as peptide factors are able to induce its conversion to a state whi ch is capable of up-regulating the transcription of key growth-promoti ng genes.