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

Abstract

Transgenic (TG) mice expressing the Simian virus 40 T-antigen under the control of the murine inhibin-a promoter (Inha/Tag) develop granulosa and Leydig cell tumors at the age of 5-6 months, with 100% penetrance. When these mice are gonadectomized, they develop adrenocortical tumors. Suppression of gonadotropin secretion inhibits the tumorigenesis in the gonads of intact animals and in the adrenals after gonadectomy. To study further the role of luteinizing hormone (LH) in gonadal and adrenal tumorigenesis, a double TG mouse model was generated by crossing the Inha/Tag mice with mice producing constitutively elevated levels of LH (bLHb-CTP mice). Our results show that in double TG mice (bLHb-CTP/Inha/Tag), gonadal tumorigenesis starts earlier and progresses faster than in Inha/Tag mice. Both ovarian and testicular tumors were histologically comparable with the tumors found in Inha/Tag mice. In addition, adrenal tumorigenesis was found in intact double TG females, but not in Inha/Tag females. Inhibin-a and LH receptor (LHR) were highly expressed in tumorigenic gonadal tissues, and the elevated LH levels were shown to be associated with ectopic LHR and high inhibin-a expression in the female adrenals. We conclude that in the Inha/Tag tumor mouse model, elevated LH levels act as a tumor promoter, advancing gonadal and adrenal tumorigenesis.

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

“…It has been shown that the castrated male mice developed adrenocortical tumors more slowly than gonadectomized females along with the ectopic LHR expression (Bielinska et al 2003). Moreover, the elevated LH levels induced abundant ectopic LHR expression and acted as a tumor promoter selectively only in the intact female doublepositive TG mice, where bLHb-CTP mice producing constitutively elevated levels of LH (Risma et al 1995) were crossbred with inha/Tag TG mice (Mikola et al 2003). This never happened in the male double-positive mice (Mikola et al 2003).…”

“…The adrenal tumors and a tumor-derived cell line (Ca1) express very high levels of LHR (Kananen et al 1996a, and the growth and steroidogenesis of the adrenal tumors were shown to be dependent on LH stimulation (Mikola et al 2003). 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).…”

“…The adrenal tumors and a tumor-derived cell line (Ca1) express very high levels of LHR (Kananen et al 1996a, and the growth and steroidogenesis of the adrenal tumors were shown to be dependent on LH stimulation (Mikola et al 2003). 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.…”

Bub1 Up-Regulation and Hyperphosphorylation Promote Malignant Transformation in SV40 Tag–Induced Transgenic Mouse Models

“…There have been different reports in different tissues and models showing different mechanisms of the SV40 Tag oncogene -induced cancer development. Examples include mouse pancreatic islet carcinoma (14); neoplastic transformation of murine fibroblasts through signal transducer and activator of transcription-3 (14), p130-E2F/p107-E2F (13), and VEGF (17) gene up-regulation as SV40 Tag targeting factors in gonadal and adrenal tumorigenesis (16); and mesothelial tumor by affecting telomerase activity (44).…”

“…There seems to be ample evidence that other factors contributing to the transformation potential of SV40 Tag are yet to be fully elucidated. The ability of T antigen to deregulate cell proliferation depends on its specific interaction with a variety of host cell proteins, studies of which have led to the elucidation of many different signaling pathways in different cancer modeling systems (12)(13)(14)(15)(16)(17)(18).…”