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American Journal of Physiology.... Feb 2012Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could exert autocrine or paracrine actions on anterior pituitary cells. In...
Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could exert autocrine or paracrine actions on anterior pituitary cells. In fact, it has been observed that prolactin inhibits its own expression by lactotropes. Our hypothesis is that prolactin participates in the control of anterior pituitary cell turnover. In the present study, we explored the action of prolactin on proliferation and apoptosis of anterior pituitary cells and its effect on the expression of the prolactin receptor. To determine the activity of endogenous prolactin, we evaluated the effect of the competitive prolactin receptor antagonist Δ1-9-G129R-hPRL in vivo, using transgenic mice that constitutively and systemically express this antagonist. The weight of the pituitary gland and the anterior pituitary proliferation index, determined by BrdU incorporation, were higher in transgenic mice expressing the antagonist than in wild-type littermates. In addition, blockade of prolactin receptor in vitro by Δ1-9-G129R-hPRL increased proliferation and inhibited apoptosis of somatolactotrope GH3 cells and of primary cultures of male rat anterior pituitary cells, including lactotropes. These results suggest that prolactin acts as an autocrine/paracrine antiproliferative and proapoptotic factor in the anterior pituitary gland. In addition, anterior pituitary expression of the long isoform of the prolactin receptor, measured by real-time PCR, increased about 10-fold in transgenic mice expressing the prolactin receptor antagonist, whereas only a modest increase in the S3 short-isoform expression was observed. These results suggest that endogenous prolactin may regulate its own biological actions in the anterior pituitary by inhibiting the expression of the long isoform of the prolactin receptor. In conclusion, our observations suggest that prolactin is involved in the maintenance of physiological cell renewal in the anterior pituitary. Alterations in this physiological role of prolactin could contribute to pituitary tumor development.
Topics: Animals; Apoptosis; Cell Line; Cell Proliferation; Cells, Cultured; Gene Expression Regulation; Hormone Antagonists; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Organ Size; Pituitary Gland, Anterior; Prolactin; Protein Isoforms; RNA, Messenger; Rats; Rats, Wistar; Receptors, Prolactin; Recombinant Proteins; Signal Transduction
PubMed: 22094470
DOI: 10.1152/ajpendo.00333.2011 -
Rheumatology (Oxford, England) Dec 2016Prolactin (PRL) is a lactation-inducing hormone with immunomodulatory properties and is found at elevated levels in the serum of patients with RA and other rheumatic...
OBJECTIVES
Prolactin (PRL) is a lactation-inducing hormone with immunomodulatory properties and is found at elevated levels in the serum of patients with RA and other rheumatic diseases. The PRL receptor (PRLR) has been shown to be expressed by macrophages in atherosclerotic plaques. The aim of this study was to examine PRLR expression by synovial macrophages and its role in the regulation of macrophage activation.
METHODS
Serum monomeric 23 kDa PRL levels were measured in 119 RA patients using a fluoroimmunometric assay. PRLR expression was assessed in synovial tissue of 91 RA, 15 PsA and 8 OA patients by immunohistochemistry and digital image analysis. Double IF was used to identify PRLR-expressing cells. The effects of PRL on monocyte-derived macrophage gene expression were examined by quantitative real-time PCR and ELISA.
RESULTS
Serum PRL levels were similar in female and male RA patients. Median (interquartile range) PRLR expression was significantly higher (P < 0.05) in RA and PsA synovial tissue compared with OA. PRLR colocalized with synovial CD68 macrophages and von Willebrand factor endothelial cells. In vitro, PRLR was prominently expressed in IFN-γ-and IL-10-polarized macrophages compared with other polarizing conditions. PRL by itself had negligible effects on macrophage gene expression, but cooperated with CD40L and TNF to increase expression of pro-inflammatory genes including IL-6, IL-8 and IL-12β.
CONCLUSIONS
Synovial PRLR expression is enhanced in patients with inflammatory arthritis compared with OA, and PRL cooperates with other pro-inflammatory stimuli to activate macrophages. These results identify PRL and PRLR as potential new therapeutic targets in inflammatory arthritis.
Topics: Antigens, CD; Arthritis, Psoriatic; Arthritis, Rheumatoid; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Macrophage Activation; Macrophages; Male; Middle Aged; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptors, Prolactin; Synovial Membrane; Up-Regulation
PubMed: 27616146
DOI: 10.1093/rheumatology/kew316 -
The Oncologist May 2016Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical...
LESSONS LEARNED
Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.
BACKGROUND
Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.
METHODS
Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
RESULTS
A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.
CONCLUSION
Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Receptors, Prolactin
PubMed: 27091421
DOI: 10.1634/theoncologist.2015-0502 -
The Journal of Biological Chemistry Apr 2017Cell-surface cytokine receptors are regulated by their -interacting stimulatory and inhibitory co-receptors. We previously showed that the Ig-like cell-adhesion molecule...
Cell-surface cytokine receptors are regulated by their -interacting stimulatory and inhibitory co-receptors. We previously showed that the Ig-like cell-adhesion molecule nectin-4 -interacts with the prolactin receptor through the extracellular region and stimulates prolactin-induced prolactin receptor activation and signaling, resulting in alveolar development in the mouse mammary gland. However, it remains unknown how this interaction stimulates these effects. We show here that the -interaction of the extracellular region of nectin-4 with the prolactin receptor was not sufficient for eliciting these effects and that the cytoplasmic region of nectin-4 was also required for this interaction. The cytoplasmic region of nectin-4 directly interacted with suppressor of cytokine signaling 1 (SOCS1), but not SOCS3, JAK2, or STAT5a, and inhibited the interaction of SOCS1 with JAK2, eventually resulting in the increased phosphorylation of STAT5a. The juxtamembrane region of nectin-4 interacted with the Src homology 2 domain of SOCS1. Both the interaction of nectin-4 with the extracellular region of the prolactin receptor and the interaction of SOCS1 with the cytoplasmic region of nectin-4 were required for the stimulatory effect of nectin-4 on the prolactin-induced prolactin receptor activation. The third Ig-like domain of nectin-4 and the second fibronectin type III domain of the prolactin receptor were involved in this -interaction, and both the extracellular and transmembrane regions of nectin-4 and the prolactin receptor were required for this direct interaction. These results indicate that nectin-4 serves as a stimulatory co-receptor for the prolactin receptor by regulating the feedback inhibition of SOCS1 in the JAK2-STAT5a signaling pathway.
Topics: Animals; Cell Adhesion Molecules; Cytoplasm; Female; Fibronectins; Gene Expression Regulation; HEK293 Cells; Humans; Janus Kinase 2; Mammary Glands, Animal; Mice; Mutation; Phosphorylation; Prolactin; Receptors, Prolactin; STAT5 Transcription Factor; Signal Transduction; Suppressor of Cytokine Signaling 1 Protein; Tumor Suppressor Proteins
PubMed: 28258213
DOI: 10.1074/jbc.M116.769091 -
Pharmacology Research & Perspectives Feb 2022Endometriosis in an estrogen-dependent disease that is characterized by the presence of endometrial tissue outside the uterine cavity leading to pain and infertility in... (Comparative Study)
Comparative Study
Endometriosis in an estrogen-dependent disease that is characterized by the presence of endometrial tissue outside the uterine cavity leading to pain and infertility in many affected women. Highly efficient treatment options which create a hypo-estrogenic environment can cause side effects such as hot flushes and bone mass loss that are not favorable for premenopausal women. Previous work has demonstrated that increased local or systemic prolactin seems to be involved in the pathogenesis of endometriosis. Here we examined two prolactin receptor (PRLR) blocking antibodies in a murine endometriosis interna model which relies on the induction of systemic hyperprolactinemia in female SHN mice. The severity of the disease is determined by the degree of endometrial invasion into the myometrium. In this model, endometriosis was inhibited by clinical gold standards such as progestins and anti-estrogenic approaches. PRLR blockade completely inhibited endometriosis in this mouse model to the same extent as the anti-estrogen faslodex or the GnRH antagonist cetrorelix. In contrast to cetrorelix and faslodex, the PRLR antibodies did not decrease relative uterine weights and were thus devoid of anti-estrogenic effects. We therefore hypothesize that PRLR antibodies may present a novel and highly efficient treatment option for endometriosis with a good safety and tolerability profile. Clinical studies are on the way to test this hypothesis.
Topics: Animals; Antibodies; Disease Models, Animal; Endometriosis; Female; Fulvestrant; Gonadotropin-Releasing Hormone; Hormone Antagonists; Mice; Receptors, Prolactin
PubMed: 35084123
DOI: 10.1002/prp2.916 -
Journal of Experimental & Clinical... May 2020Prolactin receptor (PRLR) is highly expressed in a subset of human breast cancer and prostate cancer, which makes it a potential target for cancer treatment. In clinical...
BACKGROUND
Prolactin receptor (PRLR) is highly expressed in a subset of human breast cancer and prostate cancer, which makes it a potential target for cancer treatment. In clinical trials, the blockade of PRLR was shown to be safe but with poor efficacy. It is therefore urgent to develop new therapies against PRLR target. Bispecific antibodies (BsAbs) could guide immune cells toward tumor cells, and produced remarkable effects in some cancers.
METHODS
In this study, a bispecific antibody targeting both tumor antigen PRLR and T cell surface CD3 antigen (PRLR-DbsAb) was constructed by split intein mediated protein transsplicing (BAPTS) system for the first time. Its binding activity was determined by Biacore and Flow cytometry, and target-dependent T cell mediated cytotoxicity was detected using LDH release assay. ELISA was utilized to study the secretion of cytokines by immune cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of PRLR-DbsAb.
RESULTS
PRLR-DbsAb in vitro could recruit and activate T cells to promote the release of Th1 cytokines IFN- γ and TNF- α, which could kill PRLR expressed breast cancer cells. In xenograft models with breast cancer cell line T47D, NOD/SCID mice intraperitoneally injected with PRLR-DbsAb exhibited significant inhibition of tumor growth and a longer survival compared to mice treated with PRLR monoclonal antibody (PRLR mAb).
CONCLUSIONS
Both in vitro and in vivo experiments showed PRLR-DbsAb had a potential therapy of cancer treatment potential therapy for cancer. Immunotherapy may be a promising treatment against the tumor target of PRLR.
Topics: Animals; Antibodies, Bispecific; Breast Neoplasms; CD3 Complex; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Jurkat Cells; Lymphocyte Activation; MCF-7 Cells; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Receptors, Prolactin; T-Lymphocytes; Transfection; Xenograft Model Antitumor Assays
PubMed: 32398042
DOI: 10.1186/s13046-020-01564-4 -
Oncotarget Apr 2017Our early studies have shown that Estradiol (E2)/Estrogen Receptor α (ER) in a non-DNA dependent manner through complex formation with C/EBPβ/SP1 induced...
Our early studies have shown that Estradiol (E2)/Estrogen Receptor α (ER) in a non-DNA dependent manner through complex formation with C/EBPβ/SP1 induced transcriptional activation of the generic hPIII promoter and expression of the Prolactin Receptor (PRLR) receptor in MCF-7 cells. Subsequent studies demonstrated effects of unliganded ERα with requisite participation of endogenous PRL on the activation of PRLR transcription. Also, EGF/ERBB1 in the absence of PRL and E2 effectively induced upregulation of the PRLR. In this study we have delineated the transcriptional mechanism of upregulation of PRLR receptor induced by E2 incorporating knowledge of the various transcriptional upregulation modalities from our previous studies. Here, we demonstrate an essential requirement of STAT5a induced by PRL via PRLR receptor which associates at the promoter and its interaction with phoshoERα S118. Knock-down of PRL by siRNA significantly reduced E2-induced PRLR promoter activity, mRNA and protein expression, recruitment of ERα to the complex at promoter, C/EBPβ association to its DNA site and productive complex formation at hPIII promoter. The specific CDK7 inhibitor (THZ1) that attenuates E2-induced ERα phosphorylation at S118 abrogated E2-induced PRLR promoter activation. Further studies demonstrated that E2 induced cell migration was inhibited by PRL siRNA and THZ1 indicating its dependence on PRL/PRLR and CDK7, respectively. Our studies have demonstrated the essential role of endogenous PRL and CDK7 in the upregulation of PRLR by E2 and provide insights for therapeutic approaches that will mitigate the transcription/expression of PRLR and its participation in breast cancer progression fueled by E2 and PRL via their cognate receptors.
Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cyclin-Dependent Kinases; Estradiol; Estrogen Receptor alpha; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Prolactin; Promoter Regions, Genetic; Protein Binding; Receptors, Prolactin; STAT5 Transcription Factor; Transcriptional Activation; Cyclin-Dependent Kinase-Activating Kinase
PubMed: 28423697
DOI: 10.18632/oncotarget.16040 -
Circulating prolactin, MPOA prolactin receptor expression and maternal aggression in lactating rats.Behavioural Brain Research Jan 2009Maternal aggression is most intense in lactating rats from the 3rd to the 12th day postpartum. The purpose of this study was to determine if plasma prolactin (PRL) and... (Comparative Study)
Comparative Study
Maternal aggression is most intense in lactating rats from the 3rd to the 12th day postpartum. The purpose of this study was to determine if plasma prolactin (PRL) and prolactin receptor (PRL-R(L)) mRNA expression in the medial preoptic area (MPOA) of lactating rats are altered in association with maternal aggression. Lactating Sprague Dawley rats were divided into five groups and exposed for 10 min to an intruder male or to an object on postpartum day 8. Trunk blood and the brain of the dams were collected 30 or 240 min after exposure and from a non-exposed group. Lower levels of prolactin were found 30 min after the aggression test. No change was detected in the number of cells expressing PRL-R(L) mRNA by in situ hybridization histochemistry (ISHH) as a function of testing. However, the correlation between plasma PRL and PRL-R(L) mRNA expression in the mothers changed from positive in control females to negative in intruder exposed animals. These data support the concept that a maternal aggressive experience, while acutely altering PRL secretion, fails to affect PRL-R(L) mRNA expression.
Topics: Aggression; Analysis of Variance; Animals; Female; Lactation; Male; Maternal Behavior; Preoptic Area; Prolactin; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Prolactin
PubMed: 18765257
DOI: 10.1016/j.bbr.2008.08.006 -
Cellular and Molecular Life Sciences :... Oct 1998Growth hormone (GH) and prolactin (PRL) quality as lymphohaemopoietic growth and differentiation factors, and so does insulin-like growth factor (IGF)-I, which mediates... (Review)
Review
Growth hormone (GH) and prolactin (PRL) quality as lymphohaemopoietic growth and differentiation factors, and so does insulin-like growth factor (IGF)-I, which mediates many of GH activities. Although there is only limited evidence that endocrine, paracrine or autocrine GH or PRL play a role in human leukaemia and lymphoma, the expression of these factors or their receptors may have diagnostic or therapeutic implications. Indeed, the participation of GH, PRL or IGF-I in the development or progression of certain haematological malignancies or to the antitumour immune response has been documented. Examples discussed in this review include a rat lymphoma in which the PRL receptor acts as an oncogene; the rat Nb2 lymphoma, which is dependent on PRL for growth; and experiments showing that PRL stimulates natural killer cell activity and the development of lymphokine-activated killer cells.
Topics: Animals; Growth Hormone; Humans; Leukemia; Leukemia, Experimental; Lymphoma; Prolactin; Rats; Receptors, Prolactin; Receptors, Somatotropin; Signal Transduction
PubMed: 9817988
DOI: 10.1007/s000180050238 -
Molecular and Cellular Endocrinology Mar 1996In vivo and in vitro studies have indicated that the anterior pituitary hormone prolactin (PRL) is an immunoregulator and functions in the development of the neonatal...
In vivo and in vitro studies have indicated that the anterior pituitary hormone prolactin (PRL) is an immunoregulator and functions in the development of the neonatal immune system. In this study, prolactin receptor (PRL-R) expression from birth to adulthood as well as the effect of milk ingestion on the PRL-R expression were examined in splenocytes and thymocytes of neonatal rats. Three approaches were taken to measure PRL-R expression: (i) polymerase chain reaction (RT-PCR); (ii) antibody to PRL-R and Western blotting; (iii) antibody to PRL-R and flow cytometry. RT-PCR analysis revealed the short and long form of PRL-R mRNA in both spleen and thymus at every age tested. However, the long form of PRL-R mRNA was always more abundant than that of the short form. In addition, antipeptide antibody against the long form of PRL-R recognized 84 and 42 kD proteins in the spleen, but only the 84 kD protein in the thymus. A monoclonal antibody U6 recognized 38 and 40 kD proteins in both the spleen and thymus. Although the mRNA level of PRL-R was relatively low at birth and increased with age in both the spleen and thymus, the levels of protein bands detected with both antibodies correlated with development in the spleen; whereas the levels remained steady in the thymus. Therefore, we concluded that the expression of PRL-R at the protein level is developmentally regulated in the spleen but not in the thymus. Finally, milk ingestion in the first seven hours decreased the percentage of cells expressing cell surface PRL-R, suggesting that milk-borne PRL may have a direct effect on lymphocytes.
Topics: Amino Acid Sequence; Animals; Antibodies; Base Sequence; Cells, Cultured; Concanavalin A; DNA Primers; Female; Gene Expression Regulation; Lymphocytes; Milk; Mitogens; Molecular Sequence Data; Pregnancy; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, Prolactin; Spleen; Thymus Gland; Tumor Cells, Cultured
PubMed: 8734472
DOI: 10.1016/0303-7207(95)03724-1