High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin-alpha-subunit promoter/Simian virus 40 T-antigen fusion gene.
Transgenic (TG) mice expressing the Simian virus 40 T-antigen under the control of the murine inhibin-alpha promoter (Inhalpha/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 Inhalpha/Tag mice with mice producing constitutively elevated levels of LH (bLHbeta-CTP mice). Our results show that in double TG mice (bLHbeta-CTP/Inhalpha/Tag), gonadal tumorigenesis starts earlier and progresses faster than in Inhalpha/Tag mice. Both ovarian and testicular tumors were histologically comparable with the tumors found in Inhalpha/Tag mice. In addition, adrenal tumorigenesis was found in intact double TG females, but not in Inhalpha/Tag females. Inhibin-alpha 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-alpha expression in the female adrenals. We conclude that in the Inhalpha/Tag tumor mouse model, elevated LH levels act as a tumor promoter, advancing gonadal and adrenal tumorigenesis.
Mikola
Maarit
M
Department of Physiology, University of Turku, FIN-20520 Turku, Finland.
Kero
Jukka
J
Nilson
John H
JH
Keri
Ruth A
RA
Poutanen
Matti
M
Huhtaniemi
Ilpo
I
D000306:Adrenal Cortex Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D019677:Artificial Gene Fusion; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics; D005260:Female; D006106:Granulosa Cell Tumor / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006728:Hormones / Q000097:blood; D007265:Inhibins / Q000096:biosynthesis / Q000235:genetics*; D007984:Leydig Cell Tumor / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007986:Luteinizing Hormone / Q000096:biosynthesis; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D011974:Receptors, LH / Q000096:biosynthesis / Q000235:genetics; D013539:Simian virus 40 / Q000276:immunology; D013736:Testicular Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
D000952:Antigens, Polyomavirus Transforming; D018997:Chorionic Gonadotropin, beta Subunit, Human; D006728:Hormones; D037101:Luteinizing Hormone, beta Subunit; D012333:RNA, Messenger; D011974:Receptors, LH; C094377:inhibin-alpha subunit; D007265:Inhibins; D007986:Luteinizing Hormone