Suppression of Gonadotropins Inhibits Gonadal Tumorigenesis in Mice Transgenic for the Mouse Inhibin  -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.

High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin-α-subunit promoter/Simian virus 40 T-antigen fusion gene

“…The finding of high LHR expression in adrenal tumors of Inha/Tag mice evoked a question about the role of gonadotropins in adrenal tumorigenesis. We later showed that either pharmacologically or genetically induced hypogonadotropic hypogonadism prevented both gonadal and adrenal tumor development in gonad-intact Inha/Tag mice (Kananen et al, 1997), thus supporting a role for gonadotropins in tumor development. In addition, the effect of testosterone on tumorigenesis was excluded (Rilianawati et al, 2000).…”

Adrenocortical tumorigenesis, luteinizing hormone receptor and transcription factors GATA-4 and GATA-6

“…It has been shown that 12 inhibin α knockout mice develop spontaneous gonadal tumors and if gonadectomized prepubertally (<6 weeks of age), they develop adrenal tumors with 99% penetrance (Matzuk et al 1994). Based on the inh -/-observations it was initially suggested that either the overexpression of gonadotropins or the lack of some gonadal factor might be the cause of tumor formation after gonadectomy (Matzuk et al 1994, Kananen et al 1996, Kananen et al 1997. Later studies have indicated that the development of tumors requires a high level of LH (Kero et al 2000) and a drop in the levels of gonadal activin, which normally inhibits the adrenal tumor growth by apoptosis (Beuschlein et al 2003).…”

“…If functional gonadectomy was induced by administration of a GnRH antagonist or by crossbreeding the transgenic mice into the hypogonadotropic hpg genetic background, neither gonadal nor adrenal tumors appeared [10]. This finding led to the hypothesis, that tumor development is related to elevated gonadotropin secretion, which is the distinct difference between the surgical and functional gonadectomy models (Kananen et al 1997). This high secretion of gonadotropins was thus proposed to stimulate the expression of LHR in tumors upon the malignization process .…”

“…Even if rare, the human adrenocortical tumors are gonadotropin responsive (Givens et al 1975, de Lange et al 1980, Leinonen et al 1991 (also see above). They may also express some common neuroectodermal and steroidogenic enzymes like in the case of transgenic mice (Kananen et al 1996, Kananen et al 1997 potentially useful for identifying factors critical for adrenocortical tumorigenesis in humans and a very useful model for human adrenocortical cancer research.…”

Targeted therapy for adrenocortical tumors in transgenic mice through their LH receptor by Hecate-human chorionic gonadotropin conjugate

“…The post-castration elevation of LH levels apparently induced the ectopic LHR expression, which together with the potent oncogene Tag expression triggered adrenocortical tumorigenesis (Mikola et al 2003). LH dependence of the tumors was proven by findings that they failed to appear if the post-castration increase in gonadotropins was blocked by either treating the mice with a gonadotropin-releasing hormone antagonist or crossbreeding them to the gonadotropin-deficient hpg (hypergonadotropic) genetic background (Cattanach et al 1977, Kananen et al 1997. The adrenocortical tumors tend to grow in prepubertally gonadectomized mice by hyperplasia-adenoma-carcinoma sequence, as hyperplasia of the adrenal cortex/adrenal adenoma could be observed at the age of 4 months, whereas discernible gonadal tumors were seen only at 6 months with low metastatic incidence .…”