The role of TGF-β/Smad signaling in dopamine agonist-resistant prolactinomas.

Background: Prolactinomas are the most common secretory pituitary adenomas. The first line of treatment involves dopamine agonists (DAs); however, a subset of patients is resistant to such therapy. Recent studies suggest that dopamine can up-regulate TGF-β1 synthesis in rat pituitary lactotrophs whereas estradiol down-regulates TGF-β1. To date, the role of TGF-β/Smad signaling in DAs-resistant prolactinomas has not been explored.
Methods: High-content screening (HCS) techniques, qRT-PCR, Western blot, immunofluorescence and ELISA, were performed to determine the role of TGF-β/Smad signaling in DAs-resistant prolactinomas.
Results: We reported a significant down-regulation of TGF-β/Smad signaling cascade in DAs-resistant prolactinomas compared to normal human anterior pituitaries. Following treatment with TGF-β1, the dopamine agonist, bromocriptine, and the estrogen antagonist (ER), fulvestrant in GH3 cells, we found that TGF-β1 and fulvestrant caused significant cytotoxicity in a dose- and time-dependent manner and activated Smad3 was detected following exposure to TGF-β1 and fulvestrant. In addition, treating GH3 cells with fulvestrant increased active TGF-β1 levels and decreased PRL levels in a dose-dependent manner.
Conclusion: TGF-β/Smad signaling pathway may play an important role in DA-resistant prolactinomas and has the potential to be a viable target for the diagnosis and treatment of prolactinomas, particularly in patients who are resistant to DAs.
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