title: Suppression of gonadotropins inhibits gonadal tumorigenesis in mice transgenic for the mouse inhibin alpha-subunit promoter/simian virus 40 T-antigen fusion gene.
abstract: 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 metastasizing gonadal tumors, of granulosa/theca or Leydig cell origin, with 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 either by treatment of 3-month-old mice for 2-3 months with a GnRH antagonist (Cetrorelix, SB-75), or by cross-breeding the TG mice to the genetic background of the gonadotropin-deficient hypogonadal mutant mouse (hpg). 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 macroscopically 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 tumorigenesis, the SB-75 treatment only partially inhibited gonadal tumor growth. None of the hypogonadotropic TG mice, homozygous for the hpg mutation, developed gonadal tumors. Their gonadal histology was indistinguishable from that of the non-TG hpg mice, suggesting total inhibition of gonadal tumorigenesis in the absence of gonadotropin stimulation. Tag expression and Leydig cell hyperplasia were apparent already in the postnatal TG mice but absent in those TG mice homozygous for the hpg mutation. In conclusion, the present results indicate that the gonadal tumorigenesis in our TG mouse model starts in early age as hyperplasia in specific somatic cells. Both this, and the subsequent malignant tumor growth, are gonadotropin dependent. A sufficient level of Tag expression, a prerequisite for gonadal tumorigenesis, only occurs upon gonadotropin stimulation.
authors.affiliation: Department of Physiology, University of Turku, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Kananen
authors.lastname: Rilianawati
authors.forename: T
authors.initials: T
authors.lastname: Paukku
authors.forename: M
authors.initials: M
authors.lastname: Markkula
authors.forename: E M
authors.initials: EM
authors.lastname: Rainio
authors.forename: I
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: I
authors.initials: I
authors.lastname: Huhtanemi
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D006062:Gonadotropins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D006965:Hyperplasia; D007265:Inhibins; D007985:Leydig Cells / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D010053:Ovary / Q000473:pathology; D010455:Peptides / Q000032:analysis / Q000097:blood / Q000235:genetics*; D010902:Pituitary Gland / Q000737:chemistry; D011374:Progesterone / Q000032:analysis / Q000097:blood; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013736:Testicular Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000032:analysis / Q000097:blood; D013997:Time Factors
chemical_list: D000952:Antigens, Polyomavirus Transforming; D006062:Gonadotropins; D006727:Hormone Antagonists; D010455:Peptides; D012333:RNA, Messenger; C094377:inhibin-alpha subunit; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D011374:Progesterone; D007265:Inhibins; C062876:cetrorelix