Gonadectomy permits adrenocortical tumorigenesis in mice transgenic for the mouse inhibin alpha-subunit promoter/simian virus 40 T-antigen fusion gene: evidence for negative autoregulation of the inhibin alpha-subunit gene.

Abstract

We have developed a transgenic (TG) mouse model for gonadal tumorigenesis expressing the Simian virus 40 T-antigen (Tag) under the mouse inhibin alpha-subunit promoter. Gonadal tumors appear with 100% penetrance by the age of 5-8 months in the TG mice. When 1-month-old TG mice were gonadectomized, adrenal gland tumors were observed in each animal (12 females, 11 males) at the age of 6-8 months. No adrenal tumors were detected in gonadectomized non-TG mice (nine females, nine males) or in the intact TG mice (n > 100). The tumors appeared to originate from the X zone of the adrenal cortex. The TG mice with adrenocortical tumors had elevated serum levels of progesterone, estradiol, and immunoreactive inhibin (including dimeric forms), but corticosterone secretion was reduced. The lack of adrenal tumors in intact TG mice suggested that the tumorous gonads secrete factor(s) inhibiting adrenal tumorigenesis. As a candidate molecule, we studied the effects of inhibin, which was high in the serum of control females and TG females with ovarian tumors, as well as in TG males with testicular tumors. The DNA synthesis, as well as the levels of inhibin-alpha and Tag mRNA expression, were significantly reduced by recombinant human inhibin A in cell cultures derived from the adrenal tumors. In accordance, the expression level of inhibin-alpha mRNA in the normal adrenal gland was elevated 2 weeks after gonadectomy. These findings suggest that gonadal inhibin can down-regulate the expression of the inhibin alpha-subunit gene in the adrenal gland. When circulating inhibin is eliminated by gonadectomy, Tag expression and tumorigenesis are stimulated in the adrenal glands of the TG mice. The results demonstrate a novel mechanism of autoregulation in inhibin alpha-subunit gene expression.

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

“…Adrenal tumors were found in all the double TG females, even without macroscopic signs of metastases in other tissues, indicating that the tumors were primary and not of metastatic origin. The same conclusion was made earlier as regards adrenal tumors developing in gonadectomized inha/Tag mice (Kananen et al, 1996b).…”

“…Female bLHb-CTP mice have previously been shown to have hypertrophic adrenal glands, to produce high amounts of corticosterone and to express LHR . In this study, we found adrenal tumorigenesis in the intact double TG bLHb-CTP/Inha/Tag female mice, while in single TG Inha/Tag mice, adrenal tumors develop only after gonadectomy (Kananen et al, 1996b). Owing to the rapid growth of gonadal tumors, in the present study we could not follow the development of adrenal tumors beyond the age of 4-5 months.…”

“…As shown previously (Kananen et al, 1995(Kananen et al, , 1996a, these mice develop gonadal tumors originating from Leydig and granulosa cells, with 100% penetrance, at the age of 5-6 months. To find out whether the extragonadal tumors frequently found in these mice were primary or because of metastases of gonadal tumors, we gonadectomized neonatal mice (Kananen et al, 1996b). To our surprise, gonadectomy led to the development of adrenal gland tumors, with 100% penetrance.…”

Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage

“…Interestingly, the DPC4 gene encodes SMAD4, an important intracellular component of the signalling pathway for the inhibin/activin growth factor family (Kingsley, 1994). Recent evidence from inhibin-α knockout mice (Matzuk et al, 1994) and transgenic mice bearing an inhibin-α promoter Simian virus 40-T antigen transgene (Kananen et al, 1996) implicates the inhibin/activin family in adrenocortical tumorigenesis, with a suggestion that inhibin-α may be a tumour suppressor (Matzuk et al, 1994). Further investigation using microsatellite markers could be used to identify possible changes at these loci.…”

Production of inhibin A not B in rams: changes in plasma inhibin A during testis growth, and expression of inhibin/activin subunit mRNA and protein in adult testis

“…The ovary produces both inhibin A and B, whereas the testes in all adult males studied to date (men: Illingworth et al, 1996; chimpanzees: Kondo et al, 2000;rhesus monkeys: Mann et al, 1997;Plant et al, 1997;rats: Woodruff et al, 1996; mice: Kananen et al, 1996;hamsters: Jin et al, 2001) secrete inhibin B and there is no evidence of the presence of inhibin A in plasma. However, during development of the testes and in neonatal life, the testes do express mRNA and protein for all three inhibin subunits, α, βA and βB (rats: Tena-Sempere et al, 1999;sheep: Jarred et al, 1999;men: Majdic et al, 1997;Anderson et al, 1998a,b).…”