ALTERED GLUCOCORTICOID RECEPTOR EXPRESSION AND FUNCTION DURING MOUSE SKIN CARCINOGENESIS

Glucocorticoids are the most potent inhibitors of tumor promotion in m ouse skin, when applied with a promoting agent at the early stages of promotion. However, established skin papillomas become resistant to gr owth inhibition by glucocorticoids. Glucocorticoid control of cellular functions is mediated by the glucocorticoid receptor (GR), a well-kno wn transcription factor. Here we present data on GR expression and fun ction in mouse papillomas and squamous cell carcinomas. Tumors were pr oduced in SENCAR mice by a 7,12- dimethylbenz[a]anthracene and 12-O-te tradecanoylphorbol-13-acetate two-stage protocol. In early papillomas (after 15-20 wk of promotion), northern blotting revealed a decrease i n the CR mRNA level that was confirmed by a binding assay. However, in late papillomas (after 30-40 wk of promotion), and especially in squa mous cell carcinomas, the level of GR in both assays was similar to or higher than the GR level in normal epidermis. To test the functional capability of GR in tumors, we compared the effect of the synthetic gl ucocorticoid fluocinolone acetonide (FA) on keratinocyte proliferation and on expression of glucocorticoid-responsive genes in normal epider mis, hyperplastic skin surrounding tumors, and mouse skin papillomas. FA strongly inhibited DNA synthesis in keratinocytes in normal skin an d tumor-surrounding skin but had no effect on DNA synthesis in papillo mas. In addition, FA strongly induced metallothionein 1 expression and inhibited connexin 26 expression in skin but did not affect expressio n of these genes in tumors. These data suggest that alteration of both the expression and function of GR may be an important mechanism of tu mor promotion in skin. (C) 1997 Wiley-Liss, Inc.