Carrera-González María Pilar, Ramírez-Expósito María Jesús, de Saavedra Jose Manuel Arias, Sánchez-Agesta Rafael, Mayas María Dolores, Martínez-Martos Jose Manuel
Experimental and Clinical Physiopathology Research Group, Department of Health Sciences, Faculty of Experimental and Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, 23071, Jaén, Spain.
Tumour Biol. 2011 Jun;32(3):543-9. doi: 10.1007/s13277-010-0149-y. Epub 2011 Jan 5.
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.
乳腺癌与甲状腺疾病之间的关联已被多次报道，但这种关联背后的机制仍有待阐明。据报道，催产素（OXT）可减弱促甲状腺激素（TSH）对促甲状腺激素释放激素（TRH）的反应性释放，并通过中枢神经系统介导的作用降低血浆中TSH以及甲状腺激素的水平。催产素酶（IRAP）是据报道可水解OXT的调节性蛋白水解酶。在人类乳腺癌和N-甲基亚硝基脲（NMU）诱导的大鼠乳腺肿瘤中均已报道了IRAP活性的变化。在此，我们使用胱氨酰-β-萘酰胺作为底物，通过荧光法测量下丘脑-垂体-甲状腺轴中的IRAP活性，以及OXT的循环水平，及其与TSH和游离甲状腺素（fT4）循环水平的关系，fT4作为对照大鼠和NMU诱导的乳腺癌大鼠甲状腺功能的标志物。我们发现，NMU诱导的乳腺癌大鼠的甲状腺功能降低，这得到了血清中TSH和fT4循环水平均低于相应对照组的支持。同时，我们发现下丘脑IRAP活性降低，而OXT的循环水平升高。我们提出，乳腺癌可能通过雌激素内分泌状态的改变，通过降低IRAP活性对下丘脑的分解代谢作用，增加垂体释放OXT。因此，OXT的高循环水平降低了垂体释放TSH，进而降低了甲状腺释放甲状腺激素，这支持了乳腺癌与甲状腺功能紊乱之间的关联。
