Prolactin receptor

Signaling

The PRLR is a class 1 cytokine receptor that uses messenger pathways to control cell proliferation, migration, intracellular ion concentration and inhibit programmed cell death (apoptosis). PRLRs also have functions in the second messenger cascades, including:

• JAK-STAT pathway – the STAT protein family has been shown to have a key transduction role in cytokine receptor signalling; this pathway is initiated following the activation of PRLRs. Although there have been 4 STAT proteins identified as transducer molecules of PRLR, STAT5 is recognised as the most important transducer of PRLR isoforms, with a role in inhibiting regulation of gene transcription.
• Ras-Raf-MAPK – initiated by PRLR activation. Phosphotyrosine residues on PRLR act as binding sites for adapter proteins – these connect PRLR to the Ras/Raf/MAP kinase cascade
• JAK-RUSH pathway
• PI3K/AKT/mTOR pathway

Function

Expression of the PRLR protein is found within cells of the mammary glands in accordance with its role in lactation, but also is the subject of attention for its diverse and emerging roles by its expression in adipose tissue, pancreatic islet cell proliferation, and immune responses. The PRLR has been found to be essential for lobuloalveolar maturation of the mammary glands during pregnancy, as evidenced by the fact that PRLR knockout mice show severely impaired development of lobuloalveolar structures. Disruption of PRLR signaling pathways have been linked to tumorigenesis and breast cancer development.

Ligands

Agonists

• Prolactin
• Growth hormone
• Human placental lactogen
• Placental growth hormone
• S179D-hPRL

Antagonists

Prolactin receptor antagonists such as Del1-9-G129R-hPRL have been developed.

Dopamine agonists are currently the most common methods used for treating hyperprolactinemia. However, since dopamine agonists only negatively regulate prolactin production from the pituitary gland, a few studies have tried to develop prolactin receptor antagonists for potentially treating the dopamine-resistant local hyperprolactinemia. Δ1–9-G129R-hPRL is one of the prolactin receptor antagonists been studied. Δ1–9-G129R-hPRL as a mutant (inactivated) form of prolactin which exerts its antagonist effect by competing with prolactin to bind with prolactin receptors; thereby, inhibiting the agonist effects of prolactin on prolactin receptors. Besides molecular antagonists, antibodies can also potentially be used to inhibit prolactin receptor signaling. LFA102 is a monoclonal antibody that has been studied and tested for disrupting prolactin receptor's signaling in breast cancers and prostate cancers. Although LFA102 has been proved sufficient to reduce prolactin receptor signaling based on in vitro and in vivo (mouse) studies, LFA102 likely has low effects on limiting tumor growth (breast and prostate cancer) as shown in phase I clinical trials.

Prolactin receptor dysfunction

PRLR dysfunction has been seen to positively regulate the proliferation of malignant cells in breast cancer. Defects on prolactin receptor signalling can trigger tumour activity, rather than suppress. Signal control is monitored by a variety of genes, and the PRLR gene has been identified in the tissue of metastatic primary breast cancer cells. The defect in the gene is thought to have built a resistance to chemotherapy, and has lost the ability to regulate the apoptosis of cells with mutated DNA. This signalling defect then fails to promote the cellular differentiation, and promotes the upstream survival of the cancerous cells. In breast cancer, the survival of the breast epithelial cells resemble the malignant cells, characteristically known to have an increased proliferative rate.