ESTROGEN-RECEPTOR BLOCKADE BY THE PURE ANTIESTROGEN, ZM-182780, INDUCES DEATH OF PITUITARY-TUMOR CELLS

Our previous studies have shown that even in the absence of estrogen, the estrogen receptor (ER) is still involved in growth by way of its c onversion to a transcriptionally active state by growth inducing cytok ines. The following paper now provides evidence that under more physio logical Conditions, the ER within the GH(3) cell line used for the pre vious investigations, not only controls growth, but that transcription al activity of the receptor is required for cell survival. Therefore w hen GH(3) cells, maintained under serum and steroid replete conditions , are exposed to the pure antiestrogen ZM 182780 (10 nM), marked cell death is observed 72-120 h after first exposure; Studies on the nature of this cell death suggested that it had some of the reported charact eristics of apoptosis or programmed cell death. Removal of steroids fr om the culture medium also resulted in cell death and this was enhance d by the addition of the pure antiestrogen. Both steroid withdrawal an d ZM 182780 induced cell death was completely reversed by the inclusio n of estrogens in the steroid free culture medium. In contrast, the no n-steroidal antiestrogen, 4-hydroxytamoxifen (4-OHT) was not able to e nhance steroid withdrawal death and at 1 mu M, this compound was shown to have marked ER agonist activity. Further studies on the addition o f conditioned medium from high density GH, cell cultures, to low densi ty steroid free cells, strongly suggested that the ER within these cel ls was responsible for the production of autocrine/paracrine survival factors.