Abstract
BackgroundDopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5–18% of patients.MethodsThe exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing.ResultsUsing stringent variant calling and filtering parameters, ten somatic variants that were mainly associated with DNA repair or protein metabolic processes were identified. New resistant variants were identified in multiple genes including PRDM2, PRG4, MUC4, DSPP, DPCR1, RP1L1, MX2, POTEF, C1orf170, and KRTAP10-3. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT–qPCR) in 12 prolactinomas and 3 normal pituitary glands. The mRNA levels of PRDM2 were approximately five-fold lower in resistant prolactinomas than in responsive tumors (p < 0.05). PRDM2 protein levels were lower in resistant prolactinomas than in responsive tumors, as determined by Western blotting and immunohistochemical analysis (p < 0.05). Overexpression of PRDM2 upregulated dopamine receptor D2 (D2DR) and inhibited the phosphorylation of ERK1/2 in MMQ cells. PRDM2 showed a synergistic effect with BRC on the inhibition of prolactin (PRL) secretion and MMQ cell viability, and low PRDM2 expression was associated with tumor recurrence.ConclusionsPRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1267-0) contains supplementary material, which is available to authorized users.
Highlights
Dopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China
We used stringent variant calling and filtering parameters and identified 10 somatic mutations mainly associated with Deoxyribonucleic acid (DNA) repair or the protein metabolic process by using whole-exome sequencing in combination with homozygosity mapping in a comparative analysis of BRC-responsive and BRCresistant prolactinomas
We describe a new candidate gene associated with BRC resistance in prolactinomas, PRDM2, and show that the protein and mRNA levels of PRDM2 are lower in BRC-resistant prolactinomas than in BRC-responsive prolactinomas
Summary
Dopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. Tumors are resistant to therapy in 5–18% of patients. Pharmacological intervention is the first-line treatment and involves the use of dopamine agonists (DAs) to reduce tumor size and prolactin level. Resistance to BRC, defined as the absence of normalization of prolactin (PRL) levels despite a 15 mg daily dose of BRC during at least 3 months, has been observed in 5–18% of prolactinomas according to the literature [3,5]. Resistance to BRC therapy may involve defects in D2 dopamine receptor expression and possibly its posttranscriptional splicing [6,7]. We describe a new candidate gene associated with BRC resistance in prolactinomas, PRDM2, and show that the protein and mRNA levels of PRDM2 are lower in BRC-resistant prolactinomas than in BRC-responsive prolactinomas
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