Ramírez-Expósito María Jesús, Dueñas-Rodríguez Basilio, Carrera-González María Pilar, Navarro-Cecilia Joaquín, Martínez-Martos Jose Manuel
Experimental and Clinical Physiopathology Research Group, Department of Health Sciences, School of Experimental and Health Sciences, University of Jaén, E-23071 Jaén, Spain.
Unit of Breast Pathology, Complejo Hospitalario de Jaén, E-23007 Jaén, Spain.
Cancers (Basel). 2020 Nov 4;12(11):3252. doi: 10.3390/cancers12113252.
Insulin-regulated aminopeptidase (IRAP) is the only enzyme known to cleave oxytocin and vasopressin; however, it is also the high-affinity binding site for angiotensin IV (AngIV) receptor type 4 (AT4) ligands and it is related to insulin-dependent glucose transporters through the translocation of the glucose transporter type 4 (GLUT4). Previous studies have demonstrated an association between IRAP activity and the number and size of mammary tumors in an animal model of breast cancer (BC). Also, a highly significant increase in IRAP activity has been found in BC tissue from women patients. Here, we found no changes in circulating IRAP in premenopausal (preMP) women, but it increased significantly in postmenopausal (postMP) women not treated with neoadjuvant chemotherapy (NACH). However, in women treated with NACH, IRAP activity increased in both preMP and postMP women. Two years of follow-up indicated lower levels of IRAP activity in untreated preMP women, but a return to control levels in untreated postMP women, while IRAP activity returned to control levels in women treated with NACH. Circulating oxytocin decreased in both preMP and postMP women during the follow-up period. Differences in Oxytocin appeared between preMP and postMP women treated with NACH, but not in women who were not treated with NACH. On the contrary, circulating vasopressin increased in untreated and treated preMP and postMP women, with most of the differences related to the hormonal status as well as the neoadjuvant treatment during the two year follow-up We propose that IRAP is involved in mechanisms related not only to oxytocin and/or vasopressin regulation, but also to the local mammary RAS through AngIV and its role in glucose transportation through the IRAP/GLUT4 system.
胰岛素调节氨肽酶（IRAP）是已知唯一能裂解催产素和加压素的酶；然而，它也是血管紧张素IV（AngIV）4型受体（AT4）配体的高亲和力结合位点，并且通过4型葡萄糖转运蛋白（GLUT4）的易位与胰岛素依赖性葡萄糖转运体相关。先前的研究已在乳腺癌（BC）动物模型中证明IRAP活性与乳腺肿瘤的数量和大小之间存在关联。此外，在女性乳腺癌患者的组织中发现IRAP活性显著增加。在此，我们发现绝经前（preMP）女性的循环IRAP无变化，但在未接受新辅助化疗（NACH）的绝经后（postMP）女性中显著增加。然而，在接受NACH治疗（NACH）的女性中，preMP和postMP女性的IRAP活性均增加。两年的随访表明，未接受治疗的preMP女性的IRAP活性较低，但未接受治疗的postMP女性的IRAP活性恢复到对照水平，而接受NACH治疗的女性的IRAP活性恢复到对照水平。在随访期间，preMP和postMP女性的循环催产素均下降。接受NACH治疗的preMP和postMP女性之间的催产素存在差异，但未接受NACH治疗的女性中没有差异。相反，未接受治疗和接受治疗的preMP和postMP女性的循环加压素均增加，在两年随访期间，大多数差异与激素状态以及新辅助治疗有关。我们认为，IRAP不仅参与与催产素和/或加压素调节相关的机制，还通过AngIV参与局部乳腺肾素-血管紧张素系统（RAS）及其在通过IRAP/GLUT4系统进行葡萄糖转运中的作用。
