Identification of genes differentially expressed in prolactinomas resistant and responsive to dopamine agonists

Author(s)

Vanessa Quintas Passos

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2006-03-10

Examining board members

Marcello Delano Bronstein; Júlio Zaki Abucham Filho; Mônica Roberto Gadelha; Chin Jia Lin; Rui Monteiro de Barros Maciel

• Advisor: Marcello Delano Bronstein

Abstract

CONTEXT: Prolactin (PRL) secretion and its gene expression are inhibited by dopamine. Prolactinomas are the most common secreting pituitary adenomas, with dopamine agonists being the first choice for their treatment. However, a subset of patients is resistant to dopamine agonists. OBJECTIVE: As the mechanisms involved in dopamine agonists resistance are not fully understood, the aim of this study was to get new insights regarding the molecular differences between prolactinomas responsive and resistant to dopamine agonists. PATIENTS: Tumor tissue of 22 patients harboring prolactinomas were collected and classified as responsive or resistant (including the ones with tumor growth) according to their clinical and laboratorial response to dopamine agonists. METHODS: The expression of 7 genes was evaluated by Real Time polymerase chain reaction: dopamine receptor type 2 (DRD2), nerve growth factor beta (NGF?) and its receptor (NGFR), estrogen receptor alpha (ESR1), beta (ESR2), pituitary tumor transforming gene (PTTG) and metallothionein 3 (MT3). RESULTS: Median DRD2 and NGFR expressions of responsive patients were significantly higher compared to the resistant ones (p= 0.016 and p= 0.009, respectively). Moreover, both expressions were positively correlated with PRL decrease during treatment (r= ?0.66; p= 0.002 and r= 0.57; p= 0.017; respectively). A positive correlation was found between NGFB and DRD2 (r= 0.53; p= 0.023) and PTTG and ESR2 expressions (r= 0.66; p= 0.008). There was also a correlation between serum PRL levels before treatment and ESR2 expression (r= 0.53, p= 0.04). It was not observed correlation between MT3 and responsiveness or resistance to dopamine agonists. CONCLUSIONS: DRD2 and NGFR expressions are related to prolactinoma responsiveness to dopamine agonists whereas PTTG and ESR2 may have a role in tumor aggressiveness. The response of prolactinomas to dopamine agonists should be view as a spectrum ranging from responsive to resistant with tumor growth (AU)