ISOLATION OF PMGT1 - A GENE THAT IS REPRESSED BY ESTROGEN AND INCREASED BY ANTIESTROGENS AND ANTIPROGESTINS

In order to isolate additional markers of oestrogen responsiveness in breast cancer and to study the mechanisms associated with the development of endocrine resistance, we have searched for oestrogen regulated genes. Differential hybridisation analysis of a cDNA library prepared from oestrogen-stimulated T-47D cells has led to the isolation of a sequence (pMGT1) whose expression is repressed (up to 8-fold) by oestrogen (10(-9) mol/l) and represents the first down-regulated gene to be identified by this methodology. Further studies of pMGT1 expression in MCF-7 cells has revealed that the pure antioestrogens, ICI164384 (10(-7) mol/l) and ICI182780 (10(-7) mol/l) and the antiprogestin Ru38486 (10(-7) mol/l), increase pMGT1 mRNA levels by approximately 40-50-fold relative to the value seen in cells exposed to oestrogens. Under the same conditions, pS2(pLIV2), a gene which is positively regulated by oestradiol, was almost undectable. Significantly, both tamoxifen (10(-7) mol/l), and 4-hydrcoxytamoxifen (10(-7) mol/l), failed to increase pMGT1 mRNA levels. Since cell culture studies have indicated that ICI164384 and ICI182780 are more effective than tamoxifen and 4-hydroxytamoxifen at inhibiting the growth of MCF-7 cells by mechanisms that lower their viability and sensitivity to growth factors, it is feasible that pMGT1 plays a central role in mediating these events and instigating pathways associated with cell death.