1,25-DIHYDROXYVITAMIN D-3 REGULATES ESTROGEN METABOLISM IN CULTURED KERATINOCYTES

Local estrogen metabolism may play an important role in modulating cel l development in peripheral tissues such as breast, adipose, and bone. C-19 androgens are converted to C-18 estrogens by the enzyme aromatas e, overexpression of which is associated with breast cancer. Interconv ersion of active estradiol (E-2) to inactive estrone is controlled by various isoforms of the enzyme 17 beta-hydroxysteroid dehydrogenase (1 7 beta HSD). We have studied the expression of these two enzymes in hu man keratinocytes and report rapid changes in 17 beta HSD activity in response to treatment with 1,25-dihydroxyvitamin D-3[1,25-(OH)(2)D-3]. Keratinocytes cultured in serum-free medium showed aromatase activity of 2.5 fmol/h.mg cell protein, which was unaffected by any culture tr eatment. A much higher level of 17 beta HSD activity was observed in t he keratinocytes, predominantly conversion off, to estrone (similar to 120 pmol/h.mg cell protein). This inactivation of E-2 increased in a dose-dependent fashion after treatment of the cells with antiprolifera tive doses of 1,25-(OH)(2)D-3 (0.1-200 nM). The effect of 1,25-(OH)(2) D-3 on 17 beta HSD activity was enhanced by simultaneous treatment wit h dexamethasone, which also increased the antiproliferative action of 1,25-(OH)(2)D-3. Reverse transcription-PCR and Northern analysis showe d that keratinocytes expressed messenger RNA for three 17 beta HSD iso enzymes (types I, II, and IV). Treatment with 1,25(OH)(2)D-3 (10 nM fo r 20 h) resulted in the up-regulation of messenger RNA levels for type 2 17 beta HSD. Further RNA studies combined with E-2 binding experime nts demonstrated the presence of estrogen receptors in the cultured ke ratinocytes. These data indicate that keratinocytes are potential targ ets for systemically or locally produced estrogens, which may, in turn , play a key role in the development of normal skin. In particular, we propose that 17 beta HSD isoenzymes are key target genes for 1,25-(OH )(2)D-3 in keratinocytes and may be an important feature of the antips oriatic effects of vitamin D and its analogs.