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Expert Opinion on Investigational Drugs Oct 2006Increasing evidence suggests an important role for autocrine/paracrine prolactin in breast and prostate cancers and other disease states. Prolactin production in these... (Review)
Review
Increasing evidence suggests an important role for autocrine/paracrine prolactin in breast and prostate cancers and other disease states. Prolactin production in these extrapituitary sites is not governed by dopamine agonists, a finding that has spurred the production of prolactin receptor antagonists. This review focuses on one such antagonist, S179D prolactin, which was produced by mimicking a natural antagonist, phosphorylated prolactin. S179D prolactin is a very effective growth antagonist, partly because it inhibits signalling from unmodified prolactin and partly because it produces its own intracellular signal. This signal results in cell differentiation, cell-cycle arrest or apoptosis depending on dose, duration of treatment and cellular context. S179D prolactin is also a potent antiangiogenic and initial studies have shown it to be a potent anti-inflammatory agent. In light of these additional modes of action, it is suggested that S179D prolactin should now be more aptly referred to as a selective prolactin receptor modulator.
Topics: Animals; Humans; Male; Neovascularization, Pathologic; Prolactin; Prostatic Neoplasms; Receptors, Prolactin
PubMed: 16989600
DOI: 10.1517/13543784.15.10.1257 -
Human Molecular Genetics Mar 2019Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the...
Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P < 0.0001) in prolactinoma patients than in 60 706 individuals of the Exome Aggregation Consortium cohort and 7045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type (WT) PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms.
Topics: Alleles; Amino Acid Sequence; Amino Acid Substitution; Disease Susceptibility; Everolimus; Female; Genotype; Humans; Janus Kinases; Male; Mutation; Prolactinoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptors, Prolactin; STAT Transcription Factors; Signal Transduction
PubMed: 30445560
DOI: 10.1093/hmg/ddy396 -
Nature Reviews. Endocrinology May 2015Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and... (Review)
Review
Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and reproduction. Animal models have provided insights into the biology of prolactin proteins and offer compelling evidence that the different prolactin isoforms each have independent biological functions. The major isoform, 23 kDa prolactin, acts via its membrane receptor, the prolactin receptor (PRL-R), which is a member of the haematopoietic cytokine superfamily and for which the mechanism of activation has been deciphered. The 16 kDa prolactin isoform is a cleavage product derived from native prolactin, which has received particular attention as a result of its newly described inhibitory effects on angiogenesis and tumorigenesis. The discovery of multiple extrapituitary sites of prolactin secretion also increases the range of known functions of this hormone. This Review summarizes current knowledge of the biology of prolactin and its receptor, as well as its physiological and pathological roles. We focus on the role of prolactin in human pathophysiology, particularly the discovery of the mechanism underlying infertility associated with hyperprolactinaemia and the identification of the first mutation in human PRLR.
Topics: Animals; Carcinogenesis; Humans; Hyperprolactinemia; Infertility; Lactotrophs; Neovascularization, Physiologic; Prolactin; Protein Isoforms; Receptors, Prolactin; Signal Transduction
PubMed: 25781857
DOI: 10.1038/nrendo.2015.36 -
Animal Biotechnology Nov 2023A total of 266 records of buffalo raised in two experimental herds in Egypt were assessed to detect prolactin () and prolactin receptor () genes' polymorphism using...
A total of 266 records of buffalo raised in two experimental herds in Egypt were assessed to detect prolactin () and prolactin receptor () genes' polymorphism using PCR-Single Strand Conformational Polymorphism (SSCP) and PCR-Restricted Fragment Length Polymorphism (RFLP) techniques as well as to investigate their association with calf birth weight (BW), weaning weight (WW), lactation period (LP), total milk yield (TMY), stillbirth, calving ease (CE), gestation length (GL), postpartum interval to pregnancy (PPIP), calving interval (CI), and age at first calving (AFC). Predicted breeding values were estimated and used in the association with detected genotypes. A monomorphic pattern of the studied 156 bp segment was recorded and absence of its polymorphism in buffalo was corroborated. We also determined polymorphism of reflected in three loci: 2, 4, and 9. Significant differences among 9 genotypes (AA, AB, and BB) were displayed for all studied traits as well as among 2 genotypes, except for CE, while 4 genotypes significantly differed only in BW, WW, TMY, stillbirth, GL, and AFC. In practice, strong associations among genotypes of the gene and the traits of interest candidate this gene to be selective in Egyptian buffalo breeding for improving both productive and reproductive traits.
Topics: Pregnancy; Female; Animals; Prolactin; Receptors, Prolactin; Buffaloes; Egypt; Stillbirth; Genotype
PubMed: 35148254
DOI: 10.1080/10495398.2022.2028160 -
Frontiers in Endocrinology 2021Prolactin (PRL) levels are reduced in the circulation of rats with diabetes or obesity, and lower circulating levels of PRL correlate with increased prevalence of...
Prolactin (PRL) levels are reduced in the circulation of rats with diabetes or obesity, and lower circulating levels of PRL correlate with increased prevalence of diabetes and a higher risk of metabolic alterations in the clinic. Furthermore, PRL stimulates β-cell proliferation, survival, and insulin production and pregnant mice lacking PRL receptors in β-cells develop gestational diabetes. To investigate the protective effect of endogenous PRL against diabetes outside pregnancy, we compared the number of cases and severity of streptozotocin (STZ)-induced hyperglycemia between C57BL/6 mice null for the PRL receptor gene ( ) and wild-type mice ( ). STZ-treated diabetic mice showed a higher number of cases and later recovery from hyperglycemia, exacerbated glucose levels, and glucose intolerance compared to the mice counterparts. Consistent with the worsening of hyperglycemia, pancreatic islet density, β-cell number, proliferation, and survival, as well as circulating insulin levels were reduced, whereas α-cell number and pancreatic inflammation were increased in the absence of PRL signaling. Deletion of the PRL receptor did not alter the metabolic parameters in vehicle-treated animals. We conclude that PRL protects whole body glucose homeostasis by reducing β-cell loss and pancreatic inflammation in STZ-induced diabetes. Medications elevating PRL circulating levels may prove to be beneficial in diabetes.
Topics: Animals; Blood Glucose; Cell Proliferation; Cell Survival; Diabetes Mellitus, Experimental; Glucose Intolerance; Insulin; Insulin-Secreting Cells; Mice; Receptors, Prolactin
PubMed: 33746901
DOI: 10.3389/fendo.2021.619696 -
Hormones & Cancer Feb 2014Previous studies have found an association between elevated circulating prolactin levels and increased risk of breast cancer. Prolactin stimulates breast cancer cell...
Prolactin receptor expression and breast cancer: relationships with tumor characteristics among pre- and post-menopausal women in a population-based case-control study from Poland.
Previous studies have found an association between elevated circulating prolactin levels and increased risk of breast cancer. Prolactin stimulates breast cancer cell proliferation, migration, and survival via binding to the cell-surface prolactin receptor. The association of prolactin receptor expression with breast tumorigenesis remains unclear as studies that have focused on this association have had limited sample size and/or information about tumor characteristics. Here, we examined the association of prolactin expression with tumor characteristics among 736 cases, from a large population-based case-control study of breast cancer conducted in Poland (2000-2003), with detailed risk factor and pathology data. Tumors were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis of prolactin receptor expression. Association of prolactin receptor expression across strata of tumor characteristics was evaluated using χ (2) analysis and logistic regression. Prolactin receptor expression did not vary by menopausal status; therefore, data from pre- and post-menopausal women were combined in the analyses. Approximately 83 % of breast cancers were categorized as strong prolactin receptor staining. Negative/low prolactin receptor expression was independently associated with poorly differentiated (p = 1.2 × 10(-08)) and larger tumors (p = 0.0005). These associations were independent of estrogen receptor expression. This is the largest study to date in which the association of prolactin receptor expression with tumor characteristics has been evaluated. These data provide new avenues from which to explore the associations of the prolactin/prolactin receptor signaling network with breast tumorigenesis.
Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinogenesis; Carcinoma; Case-Control Studies; Cell Differentiation; Female; Humans; Logistic Models; Menopause; Middle Aged; Poland; Population Groups; Prognosis; Receptors, Prolactin; Risk Factors; Tumor Burden; Young Adult
PubMed: 24249584
DOI: 10.1007/s12672-013-0165-7 -
Hormone and Metabolic Research =... Apr 2003Prolactin is a newly recognized platelet coactivator that functions through potentiation of ADP-induced platelet activation. However, the possible association between... (Comparative Study)
Comparative Study
Prolactin is a newly recognized platelet coactivator that functions through potentiation of ADP-induced platelet activation. However, the possible association between hyperprolactinemia and venous thromboembolism (VTE) has not been systematically investigated up to now; prolactin signaling mechanisms in platelets still need to be elucidated. In this study, plasma prolactin levels in healthy subjects and patients with VTE were determined, demonstrating that patients with VTE and no other congenital risk factors had significantly increased plasma prolactin levels. Moreover, prolactinoma patients demonstrated a higher incidence of VTE than the general population. To elucidate the molecular mechanisms for the development of venous thrombosis, prolactin receptor signaling during platelet activation was investigated with a focus on ADP-stimulated G-protein-regulated signaling pathways. The short isoform of prolactin receptors was detected on platelets. Signaling through this receptor, although not directly linked to Gq-proteins, substitutes for Gq-protein regulated signaling pathways involved in platelet activation. We identified protein kinase C, a well-established signaling molecule in platelet activation, as a target molecule for prolactin signaling pathways in human platelets. Our findings indicate that hyperprolactinemia may be an important novel risk factor for VTE, suggesting that its thrombogenic effect may be mediated through enhanced platelet reactivity. Revealing the molecular mechanisms of prolactin signaling will allow the design of new antithrombotic therapies.
Topics: Adult; Aged; Blotting, Western; Flow Cytometry; Humans; Hyperprolactinemia; Middle Aged; Platelet Activation; Prolactin; Receptors, Prolactin; Risk Factors; Signal Transduction; Thromboembolism
PubMed: 12778366
DOI: 10.1055/s-2003-39479 -
Endocrinology Nov 2019The prolactin receptor (Prlr) mediates not only the multiple effects of prolactin, but also those of the placental lactogens and, in humans, some actions of growth...
The prolactin receptor (Prlr) mediates not only the multiple effects of prolactin, but also those of the placental lactogens and, in humans, some actions of growth hormone. Although Prlr expression has been reported to be widespread in the body, specific cellular expression patterns within tissues are undefined for many organs. One persisting problem in investigating Prlr function is that the protein is difficult to detect using conventional methods. To allow investigation of Prlr expression with a single cell resolution, we have recently developed a knock-in mouse strain in which Cre recombinase is expressed together with the long isoform of the Prlr using an internal ribosome entry site. When crossed to a Cre-dependent reporter mouse strain, Cre-mediated recombination will genetically label cells that acutely express the Prlr as well as cells that have transiently expressed the Prlr during development. We report here the anatomical distribution of cells which express the fluorescent reporter τ green fluorescent protein in a total of 38 organs prepared from young adult male and female Prlr reporter mice. Our results establish a resource for dissecting the functional role of Prlr in multiple murine tissues.
Topics: Animals; Endocrine Glands; Exocrine Glands; Female; Gastrointestinal Tract; Lymphatic System; Male; Mice; Receptors, Prolactin; Respiratory System; Urogenital System
PubMed: 31373638
DOI: 10.1210/en.2019-00234 -
Molecular and Cellular Endocrinology Jun 2012Prolactin is a hormone that is essential for normal reproduction and signals through two types of receptors. Not only is the classical long form of the prolactin... (Review)
Review
Prolactin is a hormone that is essential for normal reproduction and signals through two types of receptors. Not only is the classical long form of the prolactin receptor identified, but so are many short form receptors in rodents and human tissues. Mouse mutagenesis studies have offered insight into the biology of prolactin family, providing compelling evidence that the different isoforms have independent biological activity. The possibility that short forms mediate cell proliferation is important for a variety of tissues including mammary gland and ovarian follicles. This review summarizes our current knowledge about prolactin signaling and its role in reproduction through either long or short isoform receptors.
Topics: Animals; Female; Fertility; Humans; Ovary; Prolactin; Protein Binding; Protein Isoforms; Protein Multimerization; Proteolysis; Receptors, Prolactin; Signal Transduction
PubMed: 21664429
DOI: 10.1016/j.mce.2011.05.004 -
Proceedings of the Society For... Jul 1994Prolactin (PRL) and growth hormone (GH) receptors are members of a superfamily that include receptors for a number of cytokines. GH and its receptor form an unusual... (Review)
Review
Prolactin (PRL) and growth hormone (GH) receptors are members of a superfamily that include receptors for a number of cytokines. GH and its receptor form an unusual homodimer consisting of one molecule of GH and two molecules of receptor. A similar homodimer of the PRL receptor is probably required for biological effects to be seen. Using specific assays to measure the functional activity of PRL and GH receptors, a 25 amino acid juxtamembrane region has been identified as essential but not sufficient for normal action. More detailed studies have limited the region to eight amino acids, rich in prolines, that is highly conserved in many members of the receptor superfamily. Finally, GH and PRL have been shown to induce the rapid tyrosine phosphorylation of an associated kinase, Janus kinase 2, and of the receptor itself.
Topics: Animals; Humans; Macromolecular Substances; Phosphorylation; Phosphotyrosine; Receptors, Prolactin; Receptors, Somatotropin; Signal Transduction; Tyrosine
PubMed: 7517048
DOI: 10.3181/00379727-206-43759