A TRANSITION IN TRANSCRIPTIONAL ACTIVATION BY THE GLUCOCORTICOID AND RETINOIC ACID RECEPTORS AT THE TUMOR STAGE OF DERMAL FIBROSARCOMA DEVELOPMENT

In transgenic mice harboring the bovine papillomavirus genome, fibrosa rcomas arise along an experimentally accessible pathway in which norma l dermal fibroblasts progress through two pre-neoplastic stages, mild and aggressive fibromatosis, followed by a final transition to the tum or stage, We found that the glucocorticoid receptor (GR) displays only modest transcriptional regulatory activity in cells derived from the three non-tumor stages, whereas it is highly active in fibrosarcoma ce lls, Upon inoculation into mice, the aggressive fibromatosis cells pro gress to tumor cells that have high GR activity; thus, the increased t ranscriptional regulatory activity of GR correlates with the cellular transition to the tumor stage. The intracellular levels of GR, as well as its hormone-dependent nuclear translocation and specific DNA bindi ng activities, are unaltered throughout the progression, Strikingly, t he low GR activity observed in the pre-neoplastic stages cannot be ove rcome by exogenous GR introduced by co-transfection, Moreover, compari sons of primary embryo fibroblasts and their transformed derivatives r evealed a similar pattern-modest GR activity, unresponsive to overexpr essed GR protein, in the normal cells was strongly increased in the tr ansformed cells, Likewise, the retinoic acid receptor (RAR) displayed similar differential activity in the fibrosarcoma pathway, Thus, the o ncogenic transformation of fibroblasts, and likely other cell types, i s accompanied by a striking increase in the activities of transcriptio nal regulators such as GR and RAR, We suggest that normal primary cell s have a heretofore unrecognized capability to limit the magnitude of induction of gene expression.