SUPPRESSION OF GONADOTROPINS INHIBITS GONADAL TUMORIGENESIS IN MICE TRANSGENIC FOR THE MOUSE INHIBIN ALPHA-SUBUNIT PROMOTER SIMIAN-VIRUS-40T-ANTIGEN FUSION GENE

We have previously developed a transgenic (TG) mouse model expressing the Simian virus 40 T-antigen (Tag), driven by a 6-kb fragment of the mouse inhibin alpha-subunit promoter (inh-alpha). The mice develop met astasizing gonadal tumors, of granulosa/theca or Leydig cell origin, w ith 100% penetrance by the age of 5-8 months. In the present study, we examined whether the appearance and growth of the gonadal tumors are dependent on gonadotropins. Gonadotropin suppression was achieved eith er by treatment of 3-month-old mice for 2-3 months with a GnRH antagon ist (Cetrorelix, SB-75), or by crossbreeding the TG mice to the geneti c background of the gonadotropin-deficient hypogonadal mutant mouse (h pg). Gonadal tumor growth was clearly inhibited by SB-75 treatment in one of the TG mouse Lines (IT6-M), as indicated by the absence of macr oscopically visible tumors and by reduced gonadal weights. Despite the suppressed gonadotropin secretion and Tag expression, hyperplasia of testicular Leydig, and ovarian stromal cells persisted in some of the treated mice. In another TG mouse line (IT6-F), with more aggressive t umorigenesis, the SB-75 treatment only partially inhibited gonadal tum or growth. None of the hypogonadotropic TG mice, homozygous for the hp g mutation, developed gonadal tumors. Their gonadal histology was indi stinguishable from that of the non-TG hpg mice, suggesting total inhib ition of gonadal tumorigenesis in the absence of gonadotropin stimulat ion. Tag expression and Leydig cell hyperplasia were apparent already in the postnatal TG mice but absent in those TG mice homozygous for th e hpg mutation. In conclusion, the present results indicate that the g onadal tumorigenesis in our TG mouse model starts in early age as hype rplasia in specific somatic cells. Both this, and the subsequent malig nant tumor growth, are gonadotropin dependent. A sufficient level of T ag expression, a prerequisite for gonadal tumorigenesis, only occurs u pon gonadotropin stimulation.