Dopamine receptors D1 and D2 show prognostic significance and potential therapeutic applications for endometrial cancer patients
Español, Pia (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Rovira, Ramon (Institut d'Investigació Biomèdica Sant Pau)
Caruana, Pablo (Institut d'Investigació Biomèdica Sant Pau)
Luna-Guibourg, Rocío (Institut d'Investigació Biomèdica Sant Pau)
Soler, Cristina (Institut d'Investigació Biomèdica Sant Pau)
Teixeira, Natalia (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Rodríguez, Francisco (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Gallardo, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Edwards, Maria (Institut d'Investigació Biomèdica Sant Pau)
Porta, Oriol (Hospital Universitari Mútua Terrassa)
Gámez, Maria (Institut d'Investigació Biomèdica Sant Pau)
Sánchez, Olga (Institut d'Investigació Biomèdica Sant Pau)
Llurba, Elisa (Institut d'Investigació Biomèdica Sant Pau)
Corchero, Jose Luis (Universitat Autònoma de Barcelona)
Céspedes, Maria Virtudes (Institut d'Investigació Biomèdica Sant Pau)

Date:	2023
Abstract:	Catecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRβ2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy. 109 EC patients were included. The expression of the ADRβ2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability. ADRβ2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3. 47 (95%CI:1. 35-8. 88)) and overall survival (HR = 2. 98 (95%CI:1. 40-6. 34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1. 1 at 0. 5% Fa). DRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.
Grants:	Instituto de Salud Carlos III PI20/00623
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	DRD1 ; DRD2 ; Dopamine receptor ; Drug repurposing ; Endometrial cancer ; Neuromodulation ; Prognostic value ; Targeted therapy
Published in:	Gynecologic Oncology, Vol. 176 (september 2023) , p. 25-35, ISSN 1095-6859

DOI: 10.1016/j.ygyno.2023.06.019
PMID: 37437489

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles