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Review
. 2021 Oct 18;22(20):11247.
doi: 10.3390/ijms222011247.

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications

Betina Biagetti  1 , Rafael Simò  1
Affiliations
Review

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications

Betina Biagetti et al. Int J Mol Sci. .

Abstract

Prolactinoma has the highest incidence rate among patients with functional pituitary tumours. Although mostly benign, there is a subgroup that can be aggressive. Some clinical, radiological and pathology features have been associated with a poor prognostic. Therefore, it can be considered as a group of heterogeneous tumours. The aim of this paper is to give an overview of the molecular pathways involved in the behaviour of prolactinoma in order to improve our approach and gain deeper insight into the better understanding of tumour development and its management. This is essential for identifying patients harbouring aggressive prolactinoma and to establish personalised therapeutics options.

Keywords: dopamine; lactotroph tumour; molecular; prolactin; prolactinoma; receptor; review.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The dorsal and ventral side of the embryonic pituitary generate proliferative and positional signals which regulate the expression of transcription factors. The T-PIT signal differentiates the most dorsal cells into corticotropes (C). Pit1 is induced in the caudomedial region of the pituitary gland, which ultimately gives rise to somatotropes (S), lactotropes (L), and thyrotropes (T). On the ventral side when GATA, SF1, ERBa are activated, the gonadotrope lineage (G) is determined.
Figure 2
Figure 2
Control of prolactin production and secretion. Prolactin controls its own secretion through a short loop, stimulating TIDA cells and in the own lactotroph cell by an autocrine loop.
Figure 3
Figure 3
Prolactin and dopamine receptor in the lactotroph cell. After dopamine binding to dopamine receptor type 2, K+ channels are activated and adenylyl cyclase activity is inactivated, resulting in the suppression of PRL gene expression, lactotroph proliferation and a decrease in the size of hypertrophied lactotrophs. D2 via G0 also activates phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways to prevent lactotroph proliferation. The autocrine released prolactin binds to the prolactin receptor and, via the Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5), (PI3K-Akt-mTOR) or the MAPK pathways, mediates changes in transcription, differentiation and proliferation.
Figure 4
Figure 4
Dopamine receptor-deficient mice and dopamine transporter-deficient mice. D2R-deficient mice, led to hyperprolactinemia, lactotroph hyperplasia in male and adenomas in female. Dopamine transporter-deficient mice have an increased dopaminergic tone due to dopamine availability. D2R: dopamine receptor.
Figure 5
Figure 5
Nuclear oestrogen receptor (αER) and crosstalk with PRLR and D2R. Oestrogens bind to αER, which stimulates lactotroph cell growth and proliferation. Prolactin induces phosphorylation of αER (αERp), while oestrogen promotes PRLR upregulation via pERα. ERα inhibition, restores pituitary adenoma cell sensitivity to bromocriptine by activating among others D2-G0 MAPK signalling. PRLR: prolactin receptor; D2R: dopamine receptor; αERp: phosphorylated αER.
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