evaluation of prolactin receptor gene in prolactinomas patients: correlation with the response to the dopamine agonists

• Grant number: 19/21123-0
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2021
• End date: February 29, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Ericka Barbosa Trarbach
• Grantee: Ericka Barbosa Trarbach
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Andrea Glezer ; Ericka Barbosa Trarbach

Abstract

Prolactin-secreting pituitary tumors (PRL) (prolactinomas) are the most prelevant pituitary tumors and its first line treatment are dopaminergic agonists (DA), being effective in about 80% of cases. However, the remaining 20% partial or total resistance to these drugs require alternative treatment. PRL binds to its receptor (PRLR), a member of the cytokine receptor family and activates signaling pathways such as Jak2 / STAT, MAPK and phosphatidylinositol 3-kinase (PI3K) / Akt. These pathways lead to the transcription of genes that regulate cell proliferation and differentiation. PRL binding to hypothalamic PRLR stimulates the secretion of dopamine, which acts on adenohypophysis inhibiting its secretion. In PRLR-/- rat pituitary hyperplasia and tumor development were observed. PRL is also involved in pituitary cell homeostasis through its autocrine action inducing apoptosis via the Jak2 / STAT5 and Akt signaling. In recent studies, PRLR variants have been identified in patients with prolactinoma, some of which have been associated with the appearance of the tumor. Functional studies have shown that one of these variants led to increased Akt expression and proliferation and respond to everolimus, an Akt inhibitor used to treat others tumors. Thus, in this study we aim to analyze the PRLR gene in an extensive cohort of patients with prolactinomas, in order to verify its relationship with the occurrence and invasiveness of these tumors, PRLserum levels and response to DA therapy, as well as the functional characterization of the new variants found. (AU)