USE OF TISSUE-SPECIFIC PROMOTERS IN THE REGULATION OF AROMATASE CYTOCHROME-P450 GENE-EXPRESSION IN HUMAN TESTICULAR AND OVARIAN SEX CORD TUMORS, AS WELL AS IN NORMAL FETAL AND ADULT GONADS

We have previously demonstrated that the tissue-specific regulation of human aromatase cytochrome P450 (P450arom) gene expression is, in par t, the consequence of the use of tissue-specific promoters. Promoter I .1 (PI.1) and PI.2-specific transcripts are expressed in the placenta, whereas promoter II (PII) appears to be the only active promoter in t he corpus luteum. Testicular and ovarian sex cord tumors with annular tubules (SCTATs) associated with gynecomastia in prepubertal boys and isosexual precocity in girls with Peutz-Jeghers syndrome (P-JS) have b een previously reported. In the present study, we investigated the reg ulatory elements directing P450arom gene transcription in samples of S CTAT from three prepubertal boys and a girl with P-JS and an ovarian g ranulosa cell tumor from an adult woman, as well as in healthy fetal a nd adult testicular and ovarian tissues. Placental tissue was used as a control Using polymerase chain reaction linked to reverse transcript ion and northern blotting, we determined the tissue-specific use of va rious P450arom promoters by analyzing specific 5'-termini from messeng er RNA templates. Results indicate a universal gonadal promoter (PII) directs P450arom gene expression in healthy fetal and adult ovaries an d testes, as well as in SCTAT of the P-JS and an adult ovarian granulo sa cell tumor. These results are interpreted to mean that use of PII i n human ovary and testis is preserved from the fetal period into adult life as well as in transformed neoplastic Sertoli and granulosa cells . On the other hand, transcripts from placenta are specific for PI.1 ( and to a much lesser extent, PI.2). In SCTAT, immunoreactive P450arom is detected only in the cytoplasm of neoplastic cells, whereas the nor mal-appearing sex cords do not contain any immunoreactive P450arom. Th ese results further suggest that the markedly increased aromatase expr ession of these transformed neoplastic cells is not a consequence of u sing different tissue-specific promoters. Rather it appears to involve activation (or failure of inhibition) of the upstream regulatory elem ents of the same promoter, which is normally functional in all gonadal tissues, namely the proximal PII.