Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

Felix Haglund,Mensur Džabić,Robert Bränström,Adam Andreasson,Ming Lu,Vladana Vukojević,Inga-Lena Nilsson,C Christofer Juhlin,Catharina Larsson,Anders Höög,Michael A Mancini

doi:10.1371/journal.pone.0036448

Abstract

BackgroundPrimary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.Methodology/Principal FindingsPRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.ConclusionsWe demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.

Highlights

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by increased levels of serum calcium and parathyroid hormone (PTH) and symptoms of e.g. osteoporosis, kidney stones, psychological disturbances or cardiovascular disease [1,2,3]
We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours
Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of retinoic acid inducible gene-I (RIG-I) like receptor, JAK-STAT and Type II interferon signalling pathways

Summary

Introduction

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by increased levels of serum calcium and parathyroid hormone (PTH) and symptoms of e.g. osteoporosis, kidney stones, psychological disturbances or cardiovascular disease [1,2,3]. The molecular background remains unknown for the majority of the common sporadic form of PHPT, caused by a single benign parathyroid tumour. As this group most frequently affects women it is suggested that female hormones and/or their receptors may have a role in these tumours. Primary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs

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