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European Journal of Histochemistry : EJH Oct 2023Prolactin (PRL) is a hormone crucial for normal reproduction, functioning as an autocrine, paracrine, and endocrine factor. This study aimed to examine the...
Prolactin (PRL) is a hormone crucial for normal reproduction, functioning as an autocrine, paracrine, and endocrine factor. This study aimed to examine the immunolocalization and expression patterns of PRL, prolactin receptor (PRLR), and signal transducer and activator of transcription 5 (STAT5) in the ovaries of wild ground squirrels during both breeding and non-breeding periods. Significant seasonal variations were observed in ovarian weights, with higher values during the breeding season and relatively lower values during the nonbreeding season. PRL, PRLR, STAT5, and p-STAT5 were immunolocalized in granulosa cells and luteal cells during the breeding season, whereas they were exclusively found in granulosa cells during the non-breeding season. The mRNA expression levels of Prl, Prlr, and Stat5 were increased in ovarian tissues during the breeding season compared to the non-breeding season. Moreover, the mean mRNA levels of Prl, Prlr, and Stat5 exhibited a positive correlation with ovarian weights. Both circulating PRL and ovarian PRL concentrations were significantly elevated during the breeding season. Additionally, transcriptomic analysis of ovarian tissues revealed differentially expressed genes possibly associated with ovarian function and mammary gland development, including ovarian follicle development, steroid synthesis, and regulation of reproductive process. These findings suggest that PRL might play an essential endocrine, autocrine, or paracrine role in the regulation of seasonal changes in the ovarian functions in wild ground squirrels.
Topics: Female; Animals; Prolactin; Receptors, Prolactin; Seasons; Ovary; STAT5 Transcription Factor; Sciuridae; RNA, Messenger
PubMed: 37781865
DOI: 10.4081/ejh.2023.3825 -
Biomeditsinskaia Khimiia Jan 2020Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data...
Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.
Topics: Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Receptor, ErbB-2; Receptors, Androgen; Receptors, Estrogen; Receptors, Progesterone; Receptors, Prolactin
PubMed: 32116231
DOI: 10.18097/PBMC20206601089 -
General and Comparative Endocrinology Sep 2013Prolactin (PRL) has one of the broadest ranges of functions of any vertebrate hormone, and plays a critical role in regulating aspects of reproduction in widely... (Review)
Review
Prolactin (PRL) has one of the broadest ranges of functions of any vertebrate hormone, and plays a critical role in regulating aspects of reproduction in widely divergent lineages. However, while PRL structure, mode of action and functions have been well-characterised in mammals, studies of other vertebrate lineages remain incomplete. As the most diverse group of vertebrates, fish offer a particularly valuable model system for the study of the evolution of reproductive endocrine function. Here, we review the current state of knowledge on the role of prolactin in fish reproduction, which extends to migration, reproductive development and cycling, brood care behaviour, pregnancy, and nutrient provisioning to young. We also highlight significant gaps in knowledge and advocate a specific bidirectional research methodology including both observational and manipulative experiments. Focusing research efforts towards the thorough characterisation of a restricted number of reproductively diverse fish models will help to provide the foundation necessary for a more explicitly evolutionary analysis of PRL function.
Topics: Animals; Cell Movement; Fishes; Prolactin; Receptors, Prolactin; Reproduction
PubMed: 23791758
DOI: 10.1016/j.ygcen.2013.05.027 -
Endocrine Reviews May 2005There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate... (Review)
Review
There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia. In addition, increasing evidence argues for the involvement of locally produced (autocrine) PRL, perhaps even more than pituitary-secreted (endocrine) PRL, in tumor growth. Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation. To that end, several PRL receptor antagonists have been developed by introducing various mutations into its natural ligands. For all but one of these analogs, the mechanism of action involves a competition with endogenous PRL for receptor binding. Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant prolactinomas. In this review, we describe the different versions of antagonists that have been developed, with emphasis on the controversies regarding their characterization, and the limits for their potential development as a drug. The most recently developed antagonist, Delta1-9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients.
Topics: Animals; Breast Neoplasms; Disease Models, Animal; Female; Humans; Male; Prostatic Neoplasms; Receptors, Prolactin
PubMed: 15814850
DOI: 10.1210/er.2004-0016 -
The Journal of Neuroscience : the... Nov 2022Parental care is critical for successful reproduction in mammals. Recent work has implicated the hormone prolactin in regulating male parental behavior, similar to its...
Parental care is critical for successful reproduction in mammals. Recent work has implicated the hormone prolactin in regulating male parental behavior, similar to its established role in females. Male laboratory mice show a mating-induced suppression of infanticide (normally observed in virgins) and onset of paternal behavior 2 weeks after mating. Using this model, we sought to investigate how prolactin acts in the forebrain to regulate paternal behavior. First, using c-fos immunoreactivity in prolactin receptor (Prlr) -IRES-Cre-tdtomato reporter mouse sires, we show that the circuitry activated during paternal interactions contains prolactin-responsive neurons in multiple sites, including the medial preoptic nucleus, bed nucleus of the stria terminalis, and medial amygdala. Next, we deleted from three prominent cell types found in these regions: glutamatergic, GABAergic, and CaMKIIα. Prlr deletion from CaMKIIα, but not glutamatergic or GABAergic cells, had a profound effect on paternal behavior as none of these KO males completed the pup-retrieval task. Prolactin was increased during mating, but not in response to pups, suggesting that the mating-induced secretion of prolactin is important for establishing the switch from infanticidal to paternal behavior. Pharmacological blockade of prolactin secretion at mating, however, had no effect on paternal behavior. In contrast, suppressing prolactin secretion at the time of pup exposure resulted in failure to retrieve pups, with exogenous prolactin administration rescuing this behavior. Together, our data show that paternal behavior in sires is dependent on basal levels of circulating prolactin acting at the time of interaction with pups, mediated through Prlr on CaMKIIα-expressing neurons. Parental care is critical for offspring survival. Compared with maternal care, however, the neurobiology of paternal care is less well understood. Here we show that the hormone prolactin, which is most well known for its female-specific role in lactation, has a role in the male brain to promote paternal behavior. In the absence of prolactin signaling specifically during interactions with pups, father mice fail to show normal retrieval behavior of pups. These data demonstrate that prolactin has a similar action in both males and females to promote parental care.
Topics: Animals; Female; Male; Mice; Brain; Maternal Behavior; Paternal Behavior; Preoptic Area; Prolactin; Receptors, Prolactin
PubMed: 36163141
DOI: 10.1523/JNEUROSCI.0558-22.2022 -
Canadian Journal of Physiology and... Dec 2000We present recent information on the molecular characterization of the prolactin receptor (PRL-R) in two teleost species, tilapia (Oreochromis niloticus) and rainbow... (Comparative Study)
Comparative Study Review
We present recent information on the molecular characterization of the prolactin receptor (PRL-R) in two teleost species, tilapia (Oreochromis niloticus) and rainbow trout (Oncorhynchus mykiss), in the perspective of improved understanding of the physiological differences in the control of osmoregulatory function between these two fish species. Although our interest will mainly focus on osmoregulatory organs, we will also discuss evidence of the presence of PRL-R in other tissues such as gonads and hematopoietic organs. The first fish PRL-R was characterized in tilapia. This receptor is similar to that of the long form of mammalian PRL-R, but the most conserved region (extracellular domain) has only 53% identity with mammalian PRL-R. A rainbow trout PRL-R cDNA has been also isolated and appeared very similar in structure to tilapia PRL-R. Expression of the PRL-R gene was studied by Northern blotting for various tissues from tilapia and trout, and a unique transcript size of 3.2-3.4 kb was observed in all tissues studied (including male and female gonads, skin, brain, spleen, head, kidney, and circulating lymphocytes). Osmoregulatory organs (gills, kidney, intestine) were the richest tissues. Using in situ hybridization, PRL-R transcripts were localized in gill chloride cells, both in trout and tilapia. Analysis of PRL-R transcript levels in gills, kidney, and intestine indicated the maintenance of a high level of expression during adaptation to a hyperosmotic environment. These results support PRL being a pleiotropic hormone in fish and suggest the presence of a unique PRL-R form in tilapia and in trout. Finally, characterization of hormone receptor binding has been carried out in both species using a radioreceptor assay (in tilapia) or surface plasmon resonance (SPR) technology (in trout). These studies indicated the presence of a stable hormone-receptor complex in tilapia, while PRL binds to its receptor through an unstable homodimeric complex in trout. Thus, the characteristics of PRL binding on its receptor appear to be significantly different in tilapia and trout. Whether such differences may lead to different signal transduction mechanisms and osmoregulatory actions of PRL in these two euryhaline species merits further investigation.
Topics: Amino Acid Sequence; Animals; Gene Expression Regulation; Molecular Sequence Data; Oncorhynchus mykiss; Phylogeny; Radioligand Assay; Receptors, Prolactin; Tilapia; Water-Electrolyte Balance
PubMed: 11149385
DOI: No ID Found -
Oxford Surveys on Eukaryotic Genes 1991The identification of cDNAs encoding receptors for growth hormone and prolactin have allowed the identification of the primary structure of these receptors. The... (Review)
Review
The identification of cDNAs encoding receptors for growth hormone and prolactin have allowed the identification of the primary structure of these receptors. The expression of these receptors can be measured in various tissues by estimation of mRNA levels using cDNA probes and measurements of protein levels by radioimmunoassay or immunoblot analysis using monoclonal or polyclonal antibodies to the receptors. Site-directed mutagenesis of ligand-binding domains will lead to an understanding of the residues important for hormone binding. In addition, mutagenesis of the cytoplasmic domains of the receptors performed together with functional tests should help identify regions of the receptor involved in the process of signal transduction. Finally, the identification of the enlarged receptor family, including receptors for cytokines, should shed some light on additional functions of growth hormone prolactin, especially in regulating immune functions.
Topics: Animals; Humans; Multigene Family; Receptors, Prolactin; Receptors, Somatotropin
PubMed: 1755936
DOI: No ID Found -
Recent Progress in Hormone Research 2003Knockout (KO) mice have been created that carry null mutations of genes encoding molecules essential for prolactin (PRL) release, PRL, the receptor for prolactin (PRLR),... (Review)
Review
Knockout (KO) mice have been created that carry null mutations of genes encoding molecules essential for prolactin (PRL) release, PRL, the receptor for prolactin (PRLR), and various members of the receptor's signaling pathway. This allowed an in vivo genetic analysis of the role of PRL in target organ function. In PRLKO and PRLRKO mice, mammary ductal side branching was absent, terminal end bud (TEB)-like structures persisted at the ductal termini well into maturity, and no alveolar buds formed along the ductal tree. Transplants of recombined mammary glands formed from stromal and epithelial elements with and without PRLR showed normal development, while supplementation of progesterone levels in PRLKO animals restored ductal side branching. During pregnancy, PRLR heterozygous animals initially showed normal ductal and alveolar development. However, alveolar development stalled during late pregnancy, preventing successful lactation. This defect could be rescued by the loss of a single allele of the suppressor of cytokine signaling (SOCS) 1 gene. Transplants of recombined glands containing PRLRKO epithelium and wild-type (WT) stroma formed alveolar buds during pregnancy but showed no lobuloalveolar development. Recombinations of WT epithelium and PRLRKO stroma showed normal development, demonstrating that a direct action of the lactogenic hormones is confined to the epithelium, to promote lobuloalveolar development. Transcript profiling of epithelial transplants expressing or not expressing PRLR was used during early pregnancy to investigate the transcriptional response to lactogens underlying this defect. Such profiling has identified a number of genes with well-characterized roles in mammary development, in addition to a number of novel transcripts.
Topics: Animals; Carrier Proteins; Estrous Cycle; Female; Male; Mammary Glands, Animal; Mice; Mice, Knockout; Ovary; Pregnancy; Progesterone; Prolactin; Receptors, Prolactin; Repressor Proteins; Sexual Maturation; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Transcription, Genetic
PubMed: 12795425
DOI: 10.1210/rp.58.1.297 -
Journal of Molecular Recognition : JMR 2011The cytokine hormone prolactin has a vast number of diverse functions. Unfortunately, it also exhibits tumor growth promoting properties, which makes the development of...
The cytokine hormone prolactin has a vast number of diverse functions. Unfortunately, it also exhibits tumor growth promoting properties, which makes the development of prolactin receptor antagonists a priority. Prolactin binds to its cognate receptor with much lower affinity at low pH than at physiological pH and since the extracellular environment around solid tumors often is acidic, it is desirable to develop antagonists that have improved binding affinity at low pH. The pK(a) value of a histidine side chain is ∼6.8 making histidine residues obvious candidates for examination. From evaluation of known molecular structures of human prolactin, of the prolactin receptor and of different complexes of the two, three histidine residues in the hormone-receptor binding site 1 were selected for mutational studies. We analyzed 10 variants by circular dichroism spectroscopy, affinity and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at low pH. Pure antagonists were developed earlier and the histidine mutations were introduced within such background. The antagonistic properties were maintained and the high affinity at low pH conserved. The implications of these findings may open new areas of research in the field of prolactin cancer biology.
Topics: Calorimetry; Circular Dichroism; Histidine; Humans; Hydrogen-Ion Concentration; Models, Molecular; Mutagenesis, Site-Directed; Nuclear Magnetic Resonance, Biomolecular; Prolactin; Protein Binding; Protein Conformation; Receptors, Prolactin; Recombinant Proteins; Thermodynamics
PubMed: 20842635
DOI: 10.1002/jmr.1064 -
Biochemical Society Transactions May 2001During development, the fetus is exposed to prolactin activity from the placenta, as well as from the developing fetal pituitary. Distinct prolactin receptor isoforms,...
During development, the fetus is exposed to prolactin activity from the placenta, as well as from the developing fetal pituitary. Distinct prolactin receptor isoforms, having different cytoplasmic domains generated by alternative splicing, are expressed as development proceeds at different levels in different organs. The "long" receptors are able to mediate transduction of all signals examined, in contrast with the "short" isoforms, whose truncated cytoplasmic domains are able to mediate a much smaller repertoire of signals and can act as dominant negatives. Our studies demonstrate that, although these forms share internalization mechanisms, the long form is internalized faster, resulting in more rapid down-regulation of this form. In order to examine the mechanisms by which prolactin may exert trophic effects on its target tissues during development, we have examined the signalling pathways through which prolactin binding to the long receptor regulates the transcription of cyclin D1. Our studies reveal the importance of the JAK/STAT (Janus kinase/signal transduction and activators of transcription) pathway, and the complexity of prolactin signalling to this promoter.
Topics: Animals; Cattle; Cyclin D1; DNA-Binding Proteins; Down-Regulation; Endocytosis; Female; Gene Expression Regulation, Developmental; Janus Kinase 1; Pregnancy; Pregnancy Proteins; Prolactin; Protein Isoforms; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Receptors, Prolactin; Receptors, Somatotropin; STAT1 Transcription Factor; Signal Transduction; Trans-Activators
PubMed: 11356126
DOI: 10.1042/0300-5127:0290052