RESUMEN
PURPOSE: Carboxypeptidase-D (CPD) cleaves C-terminal arginine (Arg) to produce nitric oxide (NO). Upregulation of CPD and NO by 17ß-estradiol, prolactin (PRL), and androgen increases survival of human breast cancer (BCa) cells in vitro. To demonstrate similar events in vivo, CPD, nitrotyrosine (NT, hallmark of NO action), androgen receptor (AR), prolactin receptor (PRLR), and phospho-Stat5a (for activated PRLR) levels were evaluated in benign and malignant human breast tissues, and correlated with cell proliferation (Ki67) and BCa progression (Cullin-3) biomarkers. METHODS: Paraffin-embedded breast tissues were analyzed by immunohistochemistry (IHC). BCa progression markers in human MCF-7 and T47D BCa cell lines treated with NO donor SIN-1 or PRL, ±CPD inhibitors were analyzed by RT-qPCR and immunoblotting. RESULTS: IHC showed progressive increases in CPD, NT, Ki67, and Cullin-3 from low levels in benign tissues to high levels in ductal carcinoma in situ, low-grade, high-grade, and triple-negative BCa. CPD and NT staining were closely associated, implicating CPD in NO production. Phospho-Stat5a increased significantly from benign to high-grade BCa and was mostly nuclear. AR and PRLR were abundant in benign breast and BCa, including triple-negative tumors. SIN-1 and PRL increased VEGF-C and Runx2, but not Cullin-3, in BCa cell lines. PRL induction of VEGF-C and Runx2 was inhibited partly by CPD inhibitors, implicating NO, produced by PRL-regulated CPD, in BCa progression. CONCLUSIONS: The CPD-Arg-NO pathway contributes to BCa progression in vitro and in vivo. PRL/androgen activation of the pathway support combined AR and PRLR blockade as an additional therapy for BCa.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Carboxipeptidasas/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Factor C de Crecimiento Endotelial Vascular/genética , Andrógenos/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carboxipeptidasas/antagonistas & inhibidores , Proteínas Cullin/genética , Estradiol/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Antígeno Ki-67/genética , Células MCF-7 , Óxido Nítrico/metabolismo , Prolactina/metabolismo , Receptores Androgénicos/genética , Receptores de Prolactina/genética , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
This article provides a comprehensive review regarding undescended testicles and other related conditions. We have included background information summarizing variable clinical presentations, epidemiology, and the implications of undescended testis (UDT) on fertility and malignancy risk. This article has an emphasis on the approach to diagnosis and surgical management for the UDT. The purpose of this review is to provide readers with useful clinical tools for assessing and treating patients with cryptorchidism.