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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

Oncogene volume 22, pages 3269–3278 (2003)Cite this article

Abstract

Transgenic (TG) mice expressing the Simian virus 40 T-antigen under the control of the murine inhibin-α promoter (Inhα/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 Inhα/Tag mice with mice producing constitutively elevated levels of LH (bLHβ-CTP mice). Our results show that in double TG mice (bLHβ-CTP/Inhα/Tag), gonadal tumorigenesis starts earlier and progresses faster than in Inhα/Tag mice. Both ovarian and testicular tumors were histologically comparable with the tumors found in Inhα/Tag mice. In addition, adrenal tumorigenesis was found in intact double TG females, but not in Inhα/Tag females. Inhibin-α 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-α expression in the female adrenals. We conclude that in the Inhα/Tag tumor mouse model, elevated LH levels act as a tumor promoter, advancing gonadal and adrenal tumorigenesis.

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References

  • Adelson MD and Reece MT . (1993). Clin. Obstet. Gynecol., 36, 690–700.

  • Ala-Fossi SL, Aine R, Punnonen R and Mäenpää J . (2000). Eur. J. Gynaecol. Oncol., 21, 187–189.

  • Allen LF, Lefkowitz RJ, Caron MG and Cotecchia S . (1991). Proc. Natl. Acad. Sci. USA, 88, 11354–11358.

  • Chomczynski P and Sacchi N . (1987). Anal. Biochem., 162, 156–159.

  • de Jong FH, Grootenhuis AJ, Steenbergen J, van Sluijs FJ, Foekens JA, ten Kate FJ, Oosterhuis JW, Lamberts SW and Klijn JG . (1990). J. Steroid Biochem. Mol. Biol., 37, 863–866.

  • Ding YQ and Huhtaniemi I . (1989). Acta Endocrinol. (Copenh) 121, 46–54.

  • Dufau ML . (1998). Annu. Rev. Physiol., 60, 461–496.

  • Gaytan F, Pinilla L, Romero JL and Aguilar E . (1994). J. Endocrinol., 142, 527–534.

  • Gocze PM, Beamer WG, de Jong FH and Freeman DA . (1997). Gynecol. Oncol., 65, 143–148.

  • Healy DL, Burger HG, Mamers P, Jobling T, Bangah M, Quinn M, Grant P, Day AJ, Rome R and Campbell JJ . (1993). N. Engl. J. Med., 329, 1539–1542.

  • Herath CB, Watanabe G, Wanzhu J, Noguchi J, Akiyama K, Kuramoto K, Groome NP and Taya K . (2001). J. Androl., 22, 838–846.

  • Hogan B, Beddington R, Constantini F and Lacy E . (1994). Manipulating the Mouse Embryo. A Laboratory Manual. 2nd edn. Cold Spring Harbor Laboratory Press: New York.

    Google Scholar 

  • Huhtaniemi I . (1994). Eur. J. Endocrinol., 130, 25–31.

  • Huhtaniemi IT, Katikineni M and Catt KJ . (1981). Endocrinology, 109, 588–595.

  • Huhtaniemi I, Nikula H and Rannikko S . (1985). J. Clin. Endocrinol. Metab., 61, 698–704.

  • Iczkowski KA, Bostwick DG, Roche PC and Cheville JC . (1998). Mod. Pathol., 11, 774–779.

  • Illingworth PJ, Groome NP, Byrd W, Rainey WE, McNeilly AS, Mather JP and Bremner WJ . (1996). J. Clin. Endocrinol. Metab., 81, 1321–1325.

  • Kananen K, Markkula M, el-Hefnawy T, Zhang FP, Paukku T, Su JG, Hsueh AJ and Huhtaniemi I . (1996a). Mol. Cell. Endocrinol., 119, 135–146.

  • Kananen K, Markkula M, Mikola M, Rainio EM, McNeilly A and Huhtaniemi I . (1996b). Mol. Endocrinol., 10, 1667–1677.

  • Kananen K, Markkula M, Rainio E, Su JG, Hsueh AJ and Huhtaniemi IT . (1995). Mol. Endocrinol., 9, 616–627.

  • Kananen K, Rilianawati, Paukku T, Markkula M, Rainio EM and Huhtanemi I . (1997). Endocrinology, 138, 3521–3531.

  • Keri RA, Lozada KL, Abdul-Karim FW, Nadeau JH and Nilson JH . (2000). Proc. Natl. Acad. Sci. USA, 97, 383–387.

  • Kero J, Poutanen M, Zhang FP, Rahman N, McNicol AM, Nilson JH, Keri RA and Huhtaniemi IT . (2000). J. Clin. Invest., 105, 633–641.

  • Kuhn B and Gudermann T . (1999). Biochemistry, 38, 12490–12498.

  • Kumar TR, Palapattu G, Wang P, Woodruff TK, Boime I, Byrne MC and Matzuk MM . (1999). Mol. Endocrinol., 13, 851–865.

  • Kumar TR, Wang Y and Matzuk MM . (1996). Endocrinology, 137, 4210–4216.

  • Lambert-Messerlian GM, Steinhoff M, Zheng W, Canick JA, Gajewski WH, Seifer DB and Schneyer AL . (1997). Gynecol. Oncol., 65, 512–516.

  • Lappohn RE, Burger HG, Bouma J, Bangah M, Krans M and de Bruijn HW . (1989). N. Engl. J. Med., 321, 790–793.

  • Liu G, Duranteau L, Carel JC, Monroe J, Doyle DA and Shenker A . (1999). N. Engl. J. Med., 341, 1731–1736.

  • Lyons J, Landis CA, Harsh G, Vallar L, Grunewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E and Bourne HR et al. (1990). Science, 249, 655–659.

  • Matzuk MM, Finegold MJ, Su J-G, Hsueh AJW and Bradley A . (1992). Nature, 360, 313–319.

  • Matzuk MM, Finegold MJ, Mather JP, Krummen L, Lu H and Bradley A . (1994). Proc. Natl. Acad. Sci. USA, 91, 8817–8821.

  • Matzuk MM, Kumar TR, Shou W, Coerver KA, Lau AL, Behringer RR and Finegold MJ . (1996). Recent Prog. Horm. Res., 51, 123–157.

  • Mikola MK, Rahman NA, Paukku TH, Ahtiainen PM, Vaskivuo TE, Tapanainen JS, Poutanen M and Huhtaniemi IT . (2001). J. Endocrinol., 170, 79–90.

  • Mukherjee A, Park-Sarge OK and Mayo K . (1996). Endocrinology, 137, 3234–3245.

  • Neumann F . (1991). Mutat. Res., 248, 341–356.

  • Niswender GD, Midgley Jr AR, Monroe SE and Reichert Jr LE . (1968). Proc. Soc. Exp. Biol. Med., 128, 807–811.

  • Owens GE, Ken RA and Nilson JH . (2002). Mol. Endocrinol., 16, 1230–1242.

  • Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J and Vassart G . (1993). Nature, 365, 649–651.

  • Pei L, Dodson R, Scoderbek W, Maurer R and Mayo K . (1991). Mol. Endocrinol., 5, 521–534.

  • Rahman NA and Huhtaniemi IT . (2001). Biol. Reprod., 64, 1122–1130.

  • Rilianawati, Paukku T, Kero J, Zhang FP, Rahman N, Kananen K and Huhtaniemi I . (1998). Mol. Endocrinol., 6, 801–809.

  • Rilianawati, Kero J, Paukku T and Huhtaniemi I . (2000). J. Endocrinol., 166, 77–85.

  • Risma KA, Clay CM, Nett TM, Wagner T, Yun J and Nilson JH . (1995). Proc. Natl. Acad. Sci. USA, 92, 1322–1326.

  • Rulli SB, Kuorelahti A, Karaer O, Pelliniemi LJ, Poutanen M and Huhtaniemi I . (2002). Endocrinology, 143, 4085–4095.

  • Simon WE, Albrecht M, Hänsel M, Dietel M and Hölzel F . (1983). J. Natl. Cancer Inst., 70, 839–845.

  • Toppari J, Kaipia A, Kaleva M, Laato M, de Kretser DM, Krummen LA, Mather JP and Salmi TT . (1998). APMIS, 106, 101–112 discussion 112–113.

  • van Casteren JI, Schoonen WG and Kloosterboer HJ . (2000). Biol. Reprod., 62, 886–894.

  • Vuorento T, Lahti A, Hovatta O and Huhtaniemi I . (1989). Scand. J. Clin. Lab. Invest., 49, 395–401.

  • Willemsen W, Kruitwagen R, Bastiaans B, Hanselaar T and Rolland R . (1993). Lancet, 341, 986–988.

  • Wimalasena J, Dostal R and Meehan D . (1992). Gynecol. Oncol., 46, 345–350.

  • Wise PM, Krajnak KM and Kashon ML . (1996). Science, 273, 67–70.

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Acknowledgements

The skillful technical assistance of N Messner, J Vesa and T Laiho is gratefully acknowledged. This study was supported by grants from The Fund of the Finnish Cancer Societies, the Sigrid Jusélius Foundation, the Emil Aaltonen Foundation, the Ida Montin Foundation and the Academy of Finland.

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Authors and Affiliations

  1. Department of Physiology, University of Turku, Turku, FIN-20520, Finland

    Maarit Mikola, Matti Poutanen & Ilpo Huhtaniemi

  2. Department of Pediatrics, University of Turku, Turku, FIN-20520, Finland

    Jukka Kero

  3. Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, 44106, OH, USA

    John H Nilson & Ruth A Keri

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  1. Maarit Mikola
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  2. Jukka Kero
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  3. John H Nilson
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Correspondence to Ilpo Huhtaniemi.

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Mikola, M., Kero, J., Nilson, J. et al. 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. Oncogene 22, 3269–3278 (2003). https://doi.org/10.1038/sj.onc.1206518

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