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Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas

Hua Gao1, Fei Wang2, Xiaolei Lan3,4

  • 1Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. huagao@aliyun.com.

BMC Cancer
|April 18, 2015
PubMed
Abstract

Insights

Dopamine agonist resistance in prolactinomas may be linked to low PRDM2 expression. This downregulation is associated with tumor recurrence and reduced treatment effectiveness.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Dopamine agonists (DAs) are first-line treatments for prolactinomas, a common type of functioning pituitary adenoma.
  • Bromocriptine (BRC) is the primary DA available in China, yet 5-18% of patients exhibit resistance.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the genetic and molecular factors contributing to dopamine agonist resistance in prolactinomas.
  • To identify potential biomarkers for predicting treatment response and tumor recurrence.

Main Methods:

  • Whole-exome sequencing was performed on six responsive and six resistant prolactinomas.
  • Somatic variants were identified and filtered using stringent parameters.
  • Gene expression levels (mRNA and protein) of candidate genes, including PRDM2, were quantified using RT-qPCR, Western blotting, and immunohistochemistry.
  • Functional studies involved PRDM2 overexpression in MMQ cells to assess its effect on D2DR, ERK1/2 phosphorylation, and prolactin secretion.

Main Results:

  • Ten somatic variants, primarily related to DNA repair and protein metabolism, were identified.
  • New resistant variants were found in genes such as PRDM2, PRG4, and MUC4.
  • PRDM2 mRNA and protein levels were significantly lower in resistant prolactinomas compared to responsive tumors.
  • PRDM2 overexpression upregulated dopamine receptor D2 (D2DR), inhibited ERK1/2 phosphorylation, and synergized with BRC to reduce prolactin secretion and cell viability.
  • Low PRDM2 expression correlated with increased risk of tumor recurrence.

Conclusions:

  • Downregulation of PRDM2 is implicated in dopamine agonist resistance in prolactinomas.
  • PRDM2 may serve as a predictive biomarker for treatment response and tumor recurrence.
  • Targeting PRDM2 or enhancing its expression could be a potential therapeutic strategy for resistant prolactinomas.

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