Tumor Biology

, Volume 32, Issue 3, pp 543–549 | Cite as

Hypothalamus–pituitary–thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system

  • María Pilar Carrera-González
  • María Jesús Ramírez-Expósito
  • Jose Manuel Arias de Saavedra
  • Rafael Sánchez-Agesta
  • María Dolores Mayas
  • Jose Manuel Martínez-Martos
Research Article


Associations of breast cancer with diseases of the thyroid have been repeatedly reported, but the mechanism underlying this association remains to be elucidated. It has been reported that oxytocin (OXT) attenuates the thyroid-stimulating hormone (TSH) release in response to thyrotrophin-releasing hormone (TRH) and decreased plasma levels of TSH as well as the thyroid hormones by an effect mediated by the central nervous system. Oxytocinase (IRAP) is the regulatory proteolytic enzyme reported to hydrolyze OXT. Changes in IRAP activity have been reported in both human breast cancer and N-methyl-nitrosourea (NMU)-induced rat mammary tumours. Here, we measure IRAP activity fluorometrically using cystyl-β-naphthylamide as the substrate, in the hypothalamus–pituitary–thyroid axis together with the circulating levels of OXT, and its relationship with circulating levels of TSH and free thyroxine (fT4), as markers of thyroid function in control rats and rats with breast cancer induced by NMU. We found decreased thyroid function in rats with breast cancer induced by NMU, supported by the existence of lower serum circulating levels of both TSH and fT4 than their corresponding controls. Concomitantly, we found a decrease of hypothalamic IRAP activity and an increase in circulating levels of OXT. We propose that breast cancer increases OXT pituitary release by decreasing its hypothalamic catabolism through IRAP activity, probably due to the alteration of the estrogenic endocrine status. Thus, high circulating levels of OXT decreased TSH release from the pituitary, and therefore, of thyroid hormones from the thyroid, supporting the association between breast cancer and thyroid function disruption.


N-Methyl nitrosourea Thyroid-stimulating hormone Free thyroxine Oxytocin Oxytocinase Thyroid Breast cancer 



This work was supported by Junta de Andalucía through PAI BIO-296, Universidad de Jaén (grant number UJA2003/014), and Instituto de Estudios Giennenses (IEG; grant number 135/24102006).

Conflicts of interest



  1. 1.
    Michalaki V, Kondi-Pafiti A, Gennatas S, Antoniou A, Primetis H, Gennatas C. Breast cancer in association with thyroid disorders. J BUON. 2009;14(3):425–8.PubMedGoogle Scholar
  2. 2.
    Smyth PP, Smith DF, McDermott EW, Murray MJ, Geraghty JG, O’Higgins NJ. A direct relationship between thyroid enlargement and breast cancer. J Clin Endocrinol Metab. 1996;81:937–41.PubMedCrossRefGoogle Scholar
  3. 3.
    Shering SG, Zbar AP, Moriarty M, McDermot EW, O’Higgins NJ, Smyth PP. Thyroid disorders and breast cancer. Eur J Cancer Prev. 1996;5:504–6.PubMedGoogle Scholar
  4. 4.
    Giani C, Fierabracci P, Bonacci R, Gigliotti A, Campani D, De Negri F, et al. Relationship between breast cancer and thyroid disease: relevance of autoimmune thyroid disorders in breast malignancy. J Clin Endocrinol Metab. 1996;81:990–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Smyth PP. The thyroid and breast cancer: a significant association? Ann Med. 1997;29:189–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Smyth PP, Shering SG, Kilbane MT, Murray MJ, McDermott EW, Smith DF, et al. Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma. J Clin Endocrinol Metab. 1998;83:2711–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Smyth PP. Role of iodine in antioxidant defence in thyroid and breast disease. Biofactors. 2003;19:121–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Smyth PP. The thyroid, iodine and breast cancer. Breast Cancer Res. 2003;5:235–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Kuijpens JL, Nyklictek I, Louwman MW, Weetman TA, Pop VJ, Coebergh JW. Hypothyroidism might be related to breast cancer in post-menopausal women. Thyroid. 2005;15:1253–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Finley JW, Bogardus GM. Breast cancer and thyroid disease. Q Rev Surg Obstet Gynecol. 1960;17:139–47.PubMedGoogle Scholar
  11. 11.
    Adamopoulos DA, Vassilaros S, Kapolla N, Papadiamantis J, Georgiakodis F, Michalakis A. Thyroid disease in patients with benign and malignant mastopathy. Cancer. 1986;57:125–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Smyth PP. Autoimmune thyroid disease and breast cancer: a chance association? J Endocrinol Invest. 2000;23(1):42–3.PubMedGoogle Scholar
  13. 13.
    Maruchi N, Annegers JF, Kurland LT. Hashimoto’s thyroiditis and breast cancer. Mayo Clin Proc. 1976;51:263–5.PubMedGoogle Scholar
  14. 14.
    Larsen PR, Davies TF. The thyroid gland. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, editors. Textbook of endocrinology. Philadelphia: Saunders; 1998.Google Scholar
  15. 15.
    Frawley LS, Leong DA, Neill JD. Oxytocin attenuates TRH-induced TSH release from rat pituitary cells. Neuroendocrinology. 1985;40:201–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Petersson M. Oxytocin decreases plasma levels of thyroid-stimulating hormone and thyroid hormones in rats. Regul Pept. 2002;108:83–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Raggenbass M. Vasopressin- and oxytocin-induced activity in the central nervous system: electrophysiological studies using in-vitro systems. Prog Neurobiol. 2001;64(3):307–26.PubMedCrossRefGoogle Scholar
  18. 18.
    Tsujimoto M, Mizutani S, Adachi H, Kimura M, Nakazato H, Tomoda Y. Identification of human placental leucine aminopeptidase as oxytocinase. Arch Biochem Biophys. 1992;292:388–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Mizutani S, Sumi S, Oka K, Yamada R, Kurauchi O, Taira H, et al. In vitro degradation of oxytocin by pregnancy serum, placental subcellular fractions and purified placental aminopeptidases. Exp Clin Endocrinol. 1985;86:310–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Martinez JM, Prieto I, Ramirez MJ, Cueva C, Alba F, Ramirez M. Aminopeptidase activities in breast cancer tissue. Clin Chem. 1999;45:1797–802.PubMedGoogle Scholar
  21. 21.
    Carrera MP, Ramirez-Exposito MJ, Valenzuela MT, Garcia MJ, Mayas MD, Martinez-Martos JM. Serum oxytocinase activity is related to tumour growth parameters in N-methyl nitrosourea induced rat breast cancer. Life Sci. 2004;75:1369–77.PubMedCrossRefGoogle Scholar
  22. 22.
    Rivera ES, Andrade N, Martin G, Melito G, Cricco G, Mohamad N, et al. Induction of mammary tumours in rat by intraperitoneal injection of NMU: histopathology and estral cycle influence. Cancer Lett. 1994;86:223–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Gago-Dominguez M, Castelao JE. Role of lipid peroxidation and oxidative stress in the association between thyroid diseases and breast cancer. Crit Rev Oncol Hematol. 2008;68:107–14.PubMedCrossRefGoogle Scholar
  24. 24.
    Makina DM, Krasnovskaia IA. Inhibitory effect of noradrenaline on thyrostimulating activity of oxytocin in rats. Biull Eksp Biol Med. 1999;128:657–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Makina DM, Krasnovskaia IA. Morphofunctional characteristics of rat thyroid gland under the combined effect of oxytocin and adrenaline. Morfologiia. 1999;115:34–7.PubMedGoogle Scholar
  26. 26.
    Turken O, NarIn Y, DemIrbas S, Onde ME, Sayan O, KandemIr EG, et al. Breast cancer in association with thyroid disorders. Breast Cancer Res. 2003;5:R110–3.PubMedCrossRefGoogle Scholar
  27. 27.
    Ron E, Curtis R, Hoffman DA, Flannery JT. Multiple primary breast and thyroid cancer. Br J Cancer. 1984;49:87–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Dumont JE, Maenhaut C, Pirson I, Baptist M, Roger PP. Growth factors controlling the thyroid gland. Baillières Clin Endocrinol Metab. 1991;5:727–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Tosovic A, Bondeson AG, Bondeson L, Ericsson UB, Malm J, Manjer J. Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res. 2010;12(3):R33.PubMedCrossRefGoogle Scholar
  30. 30.
    Martinez JM, Ramirez MJ, Prieto I, Alba F, Ramirez M. Sex differences and in vitro effects of steroids on serum aminopeptidase activities. Peptides. 1998;19:1637–40.PubMedCrossRefGoogle Scholar
  31. 31.
    Garcia MJ, Martinez-Martos JM, Mayas MD, Carrera MP, De la Chica S, Cortes P, et al. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice. Med Chem. 2008;4:336–47.PubMedCrossRefGoogle Scholar
  32. 32.
    Carrera MP, Ramirez-Exposito MJ, Garcia MJ, Mayas MD, Martinez-Martos JM (2008) Ovarian renin-angiotensin system is involved in progesterone overproduction in rats with mammary tumours induced by n-methyl nitrosourea (NMU). ASEICA S1Google Scholar
  33. 33.
    Koohi MK, Ivell R, Walther N. Transcriptional activation of the oxytocin promoter by oestrogens uses a novel non-classical mechanism of oestrogen receptor action. J Neuroendocrinol. 2005;17(4):197–207.PubMedCrossRefGoogle Scholar
  34. 34.
    Carrera MP, Ramirez-Exposito MJ, Valenzuela MT, Garcia MJ, Mayas MD, Arias de Saavedra JM, et al. Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea. Horm Metab Res. 2005;37:74–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Cassoni P, Marrocco T, Sapino A, Allia E, Bussolati G. Oxytocin synthesis within the normal and neoplastic breast: first evidence of a local peptide source. Int J Oncol. 2006;28(5):1263–8.PubMedGoogle Scholar
  36. 36.
    Cassoni P, Sapino A, Marrocco T, Chini B, Bussolati G. Oxytocin and oxytocin receptors in cancer cells and proliferation. J Neuroendocrinol. 2004;16(4):362–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Cassoni P, Marrocco T, Deaglio S, Sapino A, Bussolati G. Biological relevance of oxytocin and oxytocin receptors in cancer cells and primary tumours. Ann Oncol. 2001;12:S37–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Carrera MP, Ramirez-Exposito MJ, Martinez-Martos JM. Actual and potential agents and biomarkers in the treatment of cancer. Anticancer Agents Med Chem. 2009;9:500–16.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2010

Authors and Affiliations

  • María Pilar Carrera-González
    • 1
  • María Jesús Ramírez-Expósito
    • 1
  • Jose Manuel Arias de Saavedra
    • 2
  • Rafael Sánchez-Agesta
    • 2
  • María Dolores Mayas
    • 1
  • Jose Manuel Martínez-Martos
    • 1
  1. 1.Experimental and Clinical Physiopathology Research Group, Department of Health Sciences, Faculty of Experimental and Health SciencesUniversity of JaénJaénSpain
  2. 2.Complejo Hospitalario de JaénJaénSpain

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