Insulin-Regulated Aminopeptidase in Women with Breast Cancer: A Role beyond the Regulation of Oxytocin and Vasopressin

Abstract

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.