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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 -
Cancer Research Apr 2017Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack...
Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of ovarian cancers express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into ovarian cancer cells via PRLR-mediated endocytosis. Compared with current clinical MRI techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant ovarian cancer. These features endow PRLR-targeted imaging with the potential to transform ovarian cancer detection. .
Topics: Animals; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Endocytosis; Female; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Mice; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Placental Lactogen; Prolactin; Receptors, Prolactin; Sensitivity and Specificity; Tissue Array Analysis
PubMed: 28202518
DOI: 10.1158/0008-5472.CAN-16-1454 -
Endocrine Reviews Feb 2008Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via... (Review)
Review
Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats and, more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution, and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans.
Topics: Animals; Female; Gene Expression Regulation; Growth; Growth Hormone; Humans; Male; Mammary Glands, Animal; Metabolism; Mice; Models, Animal; Pituitary Gland; Placental Lactogen; Pregnancy; Prolactin; Rats; Receptors, Prolactin; Reproduction; Signal Transduction
PubMed: 18057139
DOI: 10.1210/er.2007-0017 -
Diabetes Aug 2016β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin...
β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
Topics: Animals; Cell Proliferation; Cells, Cultured; Cyclin A2; Cyclin B1; Cyclin B2; Cyclin D1; Cyclin D2; Diabetes, Gestational; Female; Forkhead Box Protein M1; Insulin; Insulin-Secreting Cells; MafB Transcription Factor; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; Receptors, Prolactin; Serotonin; Signal Transduction; Tryptophan Hydroxylase
PubMed: 27217483
DOI: 10.2337/db15-1527 -
Endocrine Reviews Feb 2003The contribution of prolactin (PRL) to the pathogenesis and progression of human breast cancer at the cellular, transgenic, and epidemiological levels is increasingly... (Review)
Review
The contribution of prolactin (PRL) to the pathogenesis and progression of human breast cancer at the cellular, transgenic, and epidemiological levels is increasingly appreciated. Acting at the endocrine and autocrine/paracrine levels, PRL functions to stimulate the growth and motility of human breast cancer cells. The actions of this ligand are mediated by at least six recognized PRL receptor isoforms found on, or secreted by, human breast epithelium. The PRL/PRL receptor complex associates with and activates several signaling networks that are shared with other members of the cytokine receptor superfamily. Coupled with the recently identified intranuclear function of PRL, these networks are integrated into the in vitro and in vivo actions induced by ligand. These findings indicate that antagonists of PRL/PRL receptor interaction or PRL receptor-associated signal transduction may be of considerable utility in the treatment of human breast cancer.
Topics: Animals; Breast Neoplasms; Endocytosis; Gene Expression; Humans; Mammary Neoplasms, Animal; Prognosis; Prolactin; Receptors, Prolactin; Risk Factors; Signal Transduction
PubMed: 12588805
DOI: 10.1210/er.2001-0036 -
Breast Cancer Research : BCR 2008Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to...
INTRODUCTION
Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis. We examined the effects of the 'pure' prolactin receptor antagonist Delta1-9-G129R-hPrl (Delta1-9) on the breast cancer cell number and clonogenicity, alone and in combination with chemotherapy.
METHODS
The effects of doxorubicin, paclitaxel and Delta1-9 on the growth of breast cancer cell lines (MCF-7, T47D, MDA-MB-453, MDA-MB-468 and SK-BR-3) in monolayer culture were assessed by the sulphorhodamine B assay. Effects on clonogenicity were assessed by soft agar assay for the cell lines and by the mammosphere assay for disaggregated primary ductal carcinoma in situ samples. Dual-fluorescence immunocytochemistry was used to identify subpopulations of cells expressing the prolactin receptor and autocrine prolactin.
RESULTS
Delta1-9 as a single agent had no effect on the cell number in monolayer culture, but potentiated the cytotoxic effects of doxorubicin and paclitaxel. Doxorubicin accordingly induced expression of prolactin mRNA and protein in all five breast cancer cell lines tested. Delta1-9 alone inhibited the clonogenicity in soft agar of cell lines by ~90% and the mammosphere forming efficiency of six disaggregated primary ductal carcinoma in situ samples by a median of 56% (range 32% to 88%). Subpopulations of cells could be identified in the cell lines based on the prolactin receptor and prolactin expression.
CONCLUSION
Autocrine prolactin appears to act as an inducible survival factor in a clonogenic subpopulation of breast cancer cells. The rational combination of cytotoxics and Delta1-9 may therefore improve outcomes in breast cancer therapy by targeting this cell population.
Topics: Agar; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; DNA, Complementary; Doxorubicin; Humans; Immunohistochemistry; Paclitaxel; Prolactin; RNA, Messenger; Receptors, Prolactin; Reverse Transcriptase Polymerase Chain Reaction; Rhodamines
PubMed: 18681966
DOI: 10.1186/bcr2129 -
Genes, Brain, and Behavior Sep 2020Prolactin is often referred to as the "parental hormone" but there are examples in which prolactin and parental behavior are disconnected. One intriguing example is in...
Prolactin is often referred to as the "parental hormone" but there are examples in which prolactin and parental behavior are disconnected. One intriguing example is in avian obligate brood parasites; species exhibiting high circulating prolactin but no parental care. To understand this disconnect, we examined transcriptional and behavioral responses to prolactin in brown-headed (Molothrus ater) and bronzed (M aeneus) brood parasitic cowbirds. We first examine prolactin-dependent regulation of transcriptome wide gene expression in the preoptic area (POA), a brain region associated with parental care across vertebrates. We next examined prolactin-dependent abundance of seven parental care-related candidate genes in hypothalamic regions that are prolactin-responsive in other avian species. We found no evidence of prolactin sensitivity in cowbirds in either case. To understand this prolactin insensitivity, we compared prolactin receptor transcript abundance between parasitic and nonparasitic species and between prolactin treated and untreated cowbirds. We observed significantly lower prolactin receptor transcript abundance in brown-headed but not bronzed cowbird POA compared with a nonparasite and no prolactin-dependent changes in either parasitic species. Finally, estrogen-primed female brown-headed cowbirds with or without prolactin treatment exhibited significantly greater avoidance of nestling begging stimuli compared with untreated birds. Taken together, our results suggest that modified prolactin receptor distributions in the POA and surrounding hypothalamic regions disconnect prolactin from parental care in brood parasitic cowbirds.
Topics: Animals; Avian Proteins; Hypothalamus; Maternal Behavior; Nesting Behavior; Passeriformes; Preoptic Area; Prolactin; Receptors, Prolactin; Transcriptome
PubMed: 32198809
DOI: 10.1111/gbb.12653 -
Proceedings of the National Academy of... Mar 2019Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA...
Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.
Topics: Animals; Carcinogenesis; Celecoxib; Cell Transformation, Neoplastic; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Disease Models, Animal; Fibroblasts; Humans; Male; Mice; Nuclear Receptor Subfamily 4, Group A, Member 1; Prolactin; Prostatic Neoplasms; Retinoid X Receptors; Signal Transduction; Stromal Cells; Up-Regulation
PubMed: 30819896
DOI: 10.1073/pnas.1819303116 -
Fertility and Sterility Oct 1997To investigate intraovarian prolactin and prolactin-receptor gene expression and to assess local prolactin synthesis with emphasis on possible differences between... (Comparative Study)
Comparative Study
OBJECTIVE
To investigate intraovarian prolactin and prolactin-receptor gene expression and to assess local prolactin synthesis with emphasis on possible differences between premenopausal and postmenopausal status.
DESIGN
The RNA extracted from human premenopausal and postmenopausal tissues was subjected to reverse transcription and polymerase chain reaction by using prolactin-specific intron- and exon-spanning primers. Prolactin-receptor expression was investigated accordingly. The amplified complementary DNA fragments were analyzed by gel electrophoresis and restriction enzyme mapping. Local prolactin hormone synthesis was verified by a time-resolved immunofluorometric assay based on our monoclonal antibodies.
RESULT(S)
Prolactin and prolactin-receptor gene expression was observed in all analyzed human ovaries (n = 18). Several other human tissue specimens, such as lung and kidney, served as negative control tissues. Significantly elevated concentrations of prolactin were detected in cytosolic extracts of premenopausal (n = 6; mean +/- SD; 20.6 +/- 3.3 ng/g tissue wet weight) versus postmenopausal (n = 6; 3.6 +/- 3.0 ng/g tissue wet weight) ovaries.
CONCLUSION(S)
The human ovary not only serves as a target for endocrine prolactin action but also as a site of local prolactin hormone production. In agreement with previous reports on extrapituitary sources of prolactin, we consider prolactin as a hormone as well as an autocrine or paracrine growth or regulatory factor. Significantly increased concentrations of prolactin in premenopausal ovarian tissue verifies its role in human reproduction.
Topics: Adult; Cytosol; Female; Gene Expression; Humans; Middle Aged; Osmolar Concentration; Ovary; Postmenopause; Premenopause; Prolactin; Receptors, Prolactin
PubMed: 9341613
DOI: 10.1016/s0015-0282(97)00320-8 -
Animal Genetics Jun 2018Prolactin is an anterior pituitary peptide hormone involved in many different endocrine activities and is essential for reproductive performance. This action is mediated...
Prolactin is an anterior pituitary peptide hormone involved in many different endocrine activities and is essential for reproductive performance. This action is mediated by its receptor, the prolactin receptor, encoded by the PRLR gene. In this study, we sequenced and characterized the Mediterranean river buffalo PRLR gene (from exon 3 to 10), and we found remarkable genetic diversity. In particular, we found 24 intronic polymorphisms and 13 exonic SNPs, seven of which were non-synonymous. Furthermore, the polymorphisms identified in the 3'-UTR were investigated to establish their possible influence on microRNA binding sites. Considering all the amino acid changes and the observed allelic combinations, it is possible to deduce at least six different translations of the buffalo prolactin receptor and, consequently, the presence at the PRLR gene of at least six alleles. Furthermore, we identified a deletion of a CACTACC heptamer between nucleotides 1102 and 1103 of exon 10 (3'-UTR), and we developed an allele-specific PCR to identify the carriers of this genetic marker. Finally, the SNP g.11188A>G, detected in exon 10 and responsible for the amino acid replacement p.His328Arg, was genotyped in 308 Italian Mediterranean river buffaloes, and an association study with milk fat traits was carried out. The statistical analysis showed a tendency that approached significance for the AA genotype with higher contents of odd branched-chain fatty acids. Thus, our results suggest that the PRLR gene is a good candidate for gene association studies with qualitative traits related to buffalo milk production.
Topics: Alleles; Animals; Buffaloes; Exons; Fatty Acids; Female; Genetic Association Studies; Genotype; Haplotypes; Introns; Italy; Milk; Polymorphism, Single Nucleotide; Receptors, Prolactin
PubMed: 29569734
DOI: 10.1111/age.12645