Prolactin Receptor Gene Expression Research Articles

Significance of Duodenal Prolactin Receptor Modulation by Calcium and Vitamin D in Sulpiride-Induced Hyperprolactinemia.

Background and Objectives: Hyperprolactinemia, as a potential side-effect of some antipsychotic medications, is associated with decreased bone density and an increased risk of fractures. This study investigates whether calcium and vitamin D supplementation affects prolactin receptor (Prlr) gene expression in the duodenum, vertebrae, and kidneys of female rats with sulpiride-induced hyperprolactinemia. Materials and Methods: Twenty-one-week-old female Wistar rats were assigned to three groups: Group S consisted of ten rats who received sulpiride injections (10 mg/kg) twice daily for 6 weeks; Group D (10 rats) received daily supplementation of 50 mg calcium and 500 IU vitamin D along with sulpiride for the last 3 weeks; and Group C consisting of seven age-matched nulliparous rats serving as a control group. Real-time PCR was used to assess Prlr gene expression in the duodenum, vertebrae, and kidneys. Results: In Group S, Prlr gene expression was notably decreased in the duodenum (p < 0.01) but elevated in the vertebrae and kidneys compared to Group C. Conversely, Group D exhibited significantly increased Prlr expression in the duodenum (p < 0.01) alongside elevated expression in the vertebrae and kidneys. Conclusions: In sulpiride-induced hyperprolactinemia, decreased Prlr gene expression in the duodenum may lead to reduced intestinal calcium absorption. Consequently, prolactin may draw calcium from the skeletal system to maintain calcium balance, facilitated by increased Prlr gene expression in the vertebrae. However, vitamin D supplementation in sulpiride-induced hyperprolactinemia notably enhances Prlr gene expression in the duodenum, potentially ameliorating intestinal calcium absorption and mitigating adverse effects on bone health.

Alterations in gonadotropin, prolactin, androgen and estrogen receptor and steroidogenesis-associated gene expression in gander testes in relation to the annual period

Physiological mechanisms of seasonal changes in testicular function in birds are not fully elucidated. The balance between androgens and estrogens and testis sensitivity for gonadotropin and gonadal steroids are still unclear. The aim of the study was to examine: (1) the changes in circulating and intra-testicular steroid hormone levels and their relationship; (2) the mRNA expression of testicular gonadotropin, prolactin (PRL), progesterone (P4), androgen, and estrogen receptors, and (3) key steroidogenesis processes-related genes with immunofluorescent localization of aromatase in gander testes during the annual period. Testes from ganders (n = 25) in the first reproduction season were obtained at five breeding stages, i.e., prebreeding (PrB), peak of reproduction (PR), postbreeding (PoB), nonbreeding (NB), and onset of reproduction (OR). Males were kept under breeding conditions. It was found that plasma P4 levels decreased at the PoB and NB stages, whereas intra-testicular P4 was the highest in the NB stage. Intra-testicular estradiol (E2) levels were higher at the PoB and NB stages than the other stages, whereas testosterone (T) levels showed a nearly opposite pattern. The plasma estradiol–to–testosterone ratios were higher at the PrB, PoB and NB stages compared to other stages. The transcript abundances for luteinizing hormone receptor (LHR), PRL receptor (PRLR), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) also change in testicular tissue during the annual period. Moreover, StAR mRNA expression was upregulated at the PoB and NB stages, and CYP11A1 transcript level was the highest at the PoB stage. Stage-dependent changes in the CYP19A1 mRNA and aromatase protein levels with higher abundances of transcript at PoB and NB stages and protein at the NB stage were observed. Localization and immunofluorescent signal intensity for aromatase also differed in relation to the examined stages. It may be suggested that differential E2 levels, as well as aromatase expression and localization across annual stages are responsible for the seasonal activation/inactivation stages of testis spermatogenesis in domestic ganders. These data strongly suggest a role of aromatase in the control of gander steroidogenesis as changes in this enzyme level are associated with alternation in gonadal steroid hormones. In addition, joint action with others hormones, like PRL and LH, seems to be important in the final effect of seasonal reproduction potential.

Expression Variance of the PRLR Gene and its Association with Milk Productive Traits in Pure Holstein-Friesian and Montbeliarde×Holstein Crossbred Cattle Raised under Egyptian Condition

The objective of this study was to investigate the association between the expression level of the PRLR gene and milk production traits at different parities in pure Holstein-Friesian and Montbeliarde×Holstein crossbred cattle reared under Egyptian conditions, as well as its potential use in future breeding programs. For this purpose, eighteen healthy cows in mid lactation stage belonging to the first, second, and third parities were selected from each breed for sampling, RNA extraction, and quantitative real-time PCR. The results revealed that, the mean relative expression of prolactin receptor gene and its fold change level were significantly higher in pure Holstein-Friesian than Montbeliarde×Holstein crossbred at the level of the first three parities. In addition, there is a significant and strong positive correlation between PRLR1 and PRLR3 in pure Holstein-Friesian cattle. Significant negative correlations between PRLR2 and PRLR3, DMY3 and TMY3, were observed in Montbeliarde×Holstein crossbred cows. In conclusion, this information about the PRLR gene could be a useful indicator for the milk production trait and could be used in crossing programs that depend on genetic selection.

Prolactin Inducible Protein, but Not Prolactin, Is Present in Human Tears, Is Involved in Tear Film Quality, and Influences Evaporative Dry Eye Disease.

PurposeDecreased production of the aqueous component of the tear film is an important cause of the development of dry eye disease (DED). Tear production is influenced by hormones and hormone-like factors. Prolactin (PLR), a multifunctional pituitary gland hormone, is regularly present in the lacrimal gland of rats and rabbits. In humans, serum PLR concentration correlates with tear quality. To gain deeper insights of possible effects of PRL, prolactin receptor (PRLR) and prolactin inducible protein (PIP), we analyzed the three proteins in the human lacrimal apparatus and in reflex tears of healthy volunteers as well as patients suffering from DED.MethodsGene expression of PRLR and PIP was analyzed by RT-PCR in cadaveric human lacrimal gland and ocular surface tissues, immortalized human corneal epithelial cells (HCE and hTEPI) and human Meibomian gland epithelial cells (HMGECs). At the protein level, the expression and localization of PRL, PRLR and PIP in formalin-fixed paraffin sections of the lacrimal apparatus were studied by immunohistochemistry. In addition, tear fluid from DED patients and healthy volunteers was analyzed by ELISA to determine the concentration of PRL and PIP.ResultsRT-PCR analyses revealed gene expression of PRLR and PIP in human tissue samples of cornea, lacrimal glands, and eyelids, whereas only PIP, but not PRLR, was detectable in immortalized corneal epithelial cells. Immunohistochemistry revealed for the first time the expression and localization of PRL, PRLR, and PIP in human tissues of the lacrimal apparatus and at the ocular surface. PRL and PRLR were detectable in corneal epithelium, lacrimal glands, and Meibomian glands. Reflex tears from DED patients revealed significantly increased PIP concentrations, whereas PRL was undetectable in tears of DED patients and healthy volunteers.ConclusionPRL, PRLR, and PIP are found in the lacrimal apparatus and on the ocular surface. PIP, but not PRL, is present in human tears and appears to be involved in the physiology of tear film quality. Our clinical data revealed that PIP may affect tear quality, but further functional analyses are needed to fully elucidate the effects of PRL and PIP-associated factors in tear secretion as well as in the connection of DED.

Differential Branchial Response of Low Salinity Challenge Induced Prolactin in Active and Passive Coping Style Olive Flounder.

Stress coping styles are very common in fish, and investigations into this area can greatly improve fish welfare and promote the sustainable development of aquaculture. Although most studies have focused on the behavioral and physiological differences of these fishes, the endocrine response of different coping styles fish when undergoing salinity challenge is still unclear. We examined the physiological response in olive flounder with active coping (AC) style and passive coping (PC) style after transferred from seawater (SW) to freshwater for 0, 2, 5, 8, and 14 days. The results showed that: 1) the plasma prolactin level of FW-acclimated AC flounder was substantially higher than that of FW-acclimated PC flounder at 5, 8, and 14 days, and the branchial gene expression of prolactin receptor (PRLR) in AC flounder was slightly higher than PC flounder after transfer. While there was no remarkable difference observed in cortisol (COR) levels between AC and PC flounder. After transfer, glucocorticoid receptor (GR) expression in AC flounder was significantly higher compared with PC flounder at 8 days. 2) Branchial NKA-IR ionocytes numbers were reduced in PC flounder after transfer, while ionocytes number remain stable in AC flounder. 3) The branchial stem cell transcription factor foxi1 gene expression of AC flounder was significantly higher than PC flounder at 2, 5, and 14 days after transfer, while branchial stem cell transcription factor p63 gene expression of FW-acclimated AC flounder was only substantially higher than that of PC flounder at 5 days. 4) As an apoptosis upstream initiator, the branchial gene expression of caspase-9 in PC flounder was considerably higher than in AC flounder after transfer at 8 days. This study revealed that olive flounder with active and passive coping styles have different endocrine coping strategies after facing the low-salinity challenge. AC flounder adopt an active endocrine strategy by increasing ionocyte differentiation and prolactin secretion significantly. In contrast, PC flounder employ a passive strategy of reducing ionocytes differentiation and retaining prolactin content at a low level to reduce branchial ionocytes number.

Effects of Parental Experience and Age on Expression of Prolactin, Vasoactive Intestinal Peptide and their Receptors in a Biparental Bird (Columba livia).

As animals gain parental experience, they often show more rapid and efficient parental care responses that likely improve offspring survival and fitness. Changes in circulating hormones that underlie reproductive behaviors, including prolactin, have been found to correlate with parental experience in birds and mammals. Altered responsiveness to prolactin in key behavioral centers of the brain may also underlie the effects of experience on parental behaviors. Further, experience may also affect responsiveness to prolactin stimulatory hormones, such as hypothalamic vasoactive intestinal peptide (VIP). While experience has been shown to upregulate neural prolactin receptors and responsiveness in rodents, its effects on prolactin receptor gene expression remain unstudied in birds. To address this, we examined gene expression of pituitary prolactin, hypothalamic prolactin receptors in the preoptic area, hypothalamic VIP, and pituitary VIP receptors in both sexes of the biparental rock dove (Columba livia) when birds were not actively nesting. As age and parental experience are often confounded (i.e.,experienced parents tend to be older than their inexperienced counterparts), we measured gene expression in birds of varying combinations of age (0.6-3 years) and prior reproductive experience (0-12 chicks raised). We found that increasing experience with chicks correlated with lower PRLR expression in the preoptic area, and age correlated with lower VIP expression in birds of both sexes. Pituitary PRL and VIPR expression was not associated with parental experience or age. These results suggest there may be persistent effects of experience and age on neural responsiveness to, and regulation of, prolactin in birds.

Complement Proteins C5/C5a, Cathepsin D and Prolactin in Chondrocytes: A Possible Crosstalk in the Pathogenesis of Osteoarthritis.

Introduction: Both increased activity of the complement system (CS) and the role of the pituitary hormone prolactin (PRL) are implicated in osteoarthritis (OA) pathogenesis. Besides, Cathepsin D (CatD) activity is increased in the context of OA and can exert not only proteolytic but also non-proteolytic effects on cells. For the first time, possible crosstalk between two separate humoral systems: the CS and the PRL hormone systems in chondrocytes are examined together. Methods: Primary human articular chondrocytes (hAC) were stimulated with complement protein C5 (10 µg /mL), PRL (25 ng/mL), CatD (100 ng/mL), or anaphylatoxin C5a (25 ng/mL) for 24 h or 72 h, while unstimulated cells served as controls. In addition, co-stimulations of C5 or PRL with CatD were carried out under the same conditions. The influence of the stimulants on cell viability, cell proliferation, and metabolic activity of hAC, the chondrosarcoma cell line OUMS-27, and endothelial cells of the human umbilical cord vein (HUVEC) was investigated. Gene expression analysis of C5a receptor (C5aR1), C5, complement regulatory protein CD59, PRL, PRL receptor (PRLR), CatD, and matrix metal-loproteinases (MMP)-13 were performed using real-time PCR. Also, collagen type (Col) I, Col II, C5aR1, CD59, and PRL were detected on protein level using immunofluorescence labeling. Results: The stimulation of the hAC showed no significant impairment of the cell viability. C5, C5a, and PRL induced cell growth in OUMS-27 and HUVEC, but not in chondrocytes. CatD, as well as C5, significantly reduced the gene expression of CatD, C5aR1, C5, and CD59. PRLR gene expression was likewise impaired by C5, C5a, and PRL+CatD stimulation. On the protein level, CatD, as well as C5a, decreased Col II as well as C5aR1 synthesis. Conclusions: The significant suppression of the C5 gene expression under the influence of PRL+CatD and that of CD59 via PRL+/−CatD and conversely a suppression of the PRLR gene expression via C5 alone or C5a stimulation indicates an interrelation between the two mentioned systems. In addition, CatD and C5, in contrast to PRL, directly mediate possible negative feedback of their own gene expression.

Effects of prolactin on movement disorders and APOE, GFAP, and PRL receptor gene expression following intracerebral hemorrhage in rats.

Objective(s):Intracerebral hemorrhage (ICH) occurs mostly in the striatum. In ICH, blood prolactin level increases 3-fold. The effects of intracerebroventricular injection (ICV) of prolactin on motor disorders will be investigated. Materials and Methods:This study was performed on 32 male Wistar rats in 4 groups: sham, ICH, and prolactin with 1 μg/2 μl (P1) and 2 μg/2 μl (P2) doses. Results:The weight of animals on days 1 (P˂0.01), 3, and 7 (P˂0.05) in the sham and P2 groups increased compared with the ICH group. Neurological Deficit Score (NDS) in ICH and P1 groups decreased, and increased compared with sham and ICH groups (P˂0.001), respectively. NDS in the P1 group increased compared with the P2 group on days 1 (P˂0.0 5), 3, and 7 (P˂0.001). The duration time of rotarod in ICH and P1 groups decreased and increased compared with sham and ICH groups (P˂0.001), respectively. The duration time of rotarod in the P1 group on days 3 and 7 increased compared with the P2 group (P˂0.001). Travel distance in days 1(P˂0.01), 3(P˂0.001), and 7(P˂0.01) decreased in the ICH group. Prolactin receptor (PRL receptor) expression in ICH, P1, and P2 groups increased compared with sham and ICH groups (P˂0.001). Glial fibrillary acidic protein (GFAP) expression (P˂0.001) and apolipoprotein E (APOE) (P˂0.01) expression in the ICH group increased compared with the sham group. GFAP and APOE expression in the P1 group increased compared with the ICH group (P˂0.001). APOE expression in the P1 group increased compared with the P2 group (P˂0.001). Conclusion:According to the results, prolactin reduces movement disorders.

Different expression of LHR, PRLR, GH and IGF1 during testicular development of yak

AbstractLuteinizing hormone receptor (LHR), prolactin receptor (PRLR), growth hormone (GH) and insulin‐like growth factor 1 (IGF1) have been shown to be key regulators of germ cell development. However, the role of LHR, PRLR, GH and IGF1 in the development of yak testis remains unclear. In this study, we aimed to describe and compare gene expression and protein localization of LHR, PRLR, GH and IGF1 in the development of yak testes. Testes were collected from 6, 24, 36 and 72 months yak, and the kidney, liver, testicular, lung, skeletal muscle, heart and spleen tissues were collected from 36 months yak. The quantitative real‐time PCR (qRT‐PCR) results showed that the expression of these four genes was widely expressed in kidney, liver, testicular, lung, skeletal muscle, heart and spleen, while the LHR and PRLR were highly expressed in the kidney, skeletal muscle and testis, and higher levels of GH and IGF were expressed in spleen and testis. Moreover, the mRNA expression of these genes in adults was higher than in pre‐pubertal yak. In the testis, the LHR‐, PRLR‐, GH‐ and IGF1‐positive signals were detected in the Leydig cells of the 6 months, while the intense positive signals were discovered in Leydig cells, spermatogonia and spermatocytes of the 36 and 72 months. Thus, LHR, PRLR, GH and IGF1 may be involved in the development of spermatids and spermatocytes, and in the regulation of spermatogonia proliferation and Leydig cell function.

Prolactin and prolactin receptor expression in the HPG axis and crop during parental care in both sexes of a biparental bird (Columba livia)

During breeding, multiple circulating hormones, including prolactin, facilitate reproductive transitions in species that exhibit parental care. Prolactin underlies parental behaviors and related physiological changes across many vertebrates, including birds and mammals. While circulating prolactin levels often fluctuate across breeding, less is known about how relevant target tissues vary in their prolactin responsiveness via prolactin receptor (PRLR) expression. Recent studies have also investigated prolactin (PRL) gene expression outside of the pituitary (i.e., extra-pituitary PRL), but how PRL gene expression varies during parental care in non-pituitary tissue (e.g., hypothalamus, gonads) remains largely unknown. Further, it is unclear if and how tissue-specific PRL and PRLR vary between the sexes during biparental care. To address this, we measured PRL and PRLR gene expression in tissues relevant to parental care, the endocrine reproductive hypothalamic-pituitary- gonadal (HPG) axis and the crop (a tissue with a similar function as the mammalian mammary gland), across various reproductive stages in both sexes of a biparental bird, the rock dove (Columba livia). We also assessed how these genes responded to changes in offspring presence by adding chicks mid-incubation, simulating an early hatch when prolactin levels were still moderately low. We found that pituitary PRL expression showed similar increases as plasma prolactin levels, and detected extra-pituitary PRL in the hypothalamus, gonads and crop. Hypothalamic and gonadal PRLR expression also changed as birds began incubation. Crop PRLR expression correlated with plasma prolactin, peaking when chicks hatched. In response to replacing eggs with a novel chick mid-incubation, hypothalamic and gonadal PRL and PRLR gene expression differed significantly compared to mid-incubation controls, even when plasma prolactin levels did not differ. We also found sex differences in PRL and PRLR that suggest gene expression may allow males to compensate for lower levels in prolactin by upregulating PRLR in all tissues. Overall, this study advances our understanding of how tissue-specific changes in responsiveness to parental hormones may differ across key reproductive transitions, in response to offspring cues, and between the sexes.

Ethanol Extract of Carica papaya Leaf Can Increase Breast Milk in Lactating Rat

BACKGROUND: Carica papaya leaves (Carica papaya L) have been used empirically and traditionally as a galactogogue, but their mechanism as galactogogue is still unknown. AIM: This study aimed to analyze the effect of ethanol extract from papaya leaves on blood prolactin levels, prolactin receptor (prlr) gene expression, the number of breast alveoli and lobes of lactating rats. METHODS: This in vivo true experimental study with a post-test control group design was conducted on 24 rats with the same lactating period. They were divided into four groups consisting of six rats each. The control group was given daily standard food, whereas the three treatment groups were, respectively, given additionally ethanol extract of 0.95 mg, 1.9 mg, and 3.8 mg/200 g BW/day from day 1 to day 14 of lactation. On day 14, all of the rats were sacrificed, blood prolactin levels were measured by ELISA, prlr gene expressions were measured using RT-PCR, and numbers of breast alveoli and lobes were microscopically observed through staining histological specimens. A statistical analysis was carried out using one-way ANOVA, Tukey's test, Games–Howell test, and path analysis at 95% confidence level. RESULTS: Levels of blood prolactin levels, prlr gene expression, the number of breast alveoli, and lobes of all treatment rat groups were significantly above those of the control group (p &lt; 0.05). The increases of all parameters were consistent; the most effective dose was 1.9 mg/200 g BW. CONCLUSION: The Carica papaya leaf ethanol extract had a galactogogue effect on lactating rats by increasing blood prolactin levels, prlr gene expression, and numbers number of breast alveoli and lobes.

The Ethyl Acetate Fraction of Torbangun (Coleus amboinicus L.) Leaves Increasing Milk Production With Up-Regulated Genes Expression of Prolactin Receptor

This study aim was to determine lactagogue effect of torbangun leaves to plasma levels of lactogenic hormone and gene expression of their receptors in mammary glands of lactation rats. Lactagogue activity was evaluated by volume of milk was produced by the rats treated with commercial milk booster contained ‘katuk' leaves extract (AF), ethyl acetate fraction of torbangun leaves (EA), water extraction of torbangun leaves (AQ) and kaempferol (KP). Lactating rats (n=5) of Sprague dawley with six pups were fed with AF, EA, AQ, and KP in the amount of 50 mg/kg, 30 mg/kg, 80 mg/kg and 60 mg/kg body weight, respectively. The feed was given orally every two days and starting from day 2 after giving birth until day 28. The volume of milk was estimated by the increment pup weight after breastfed. The levels of serum lactogenic hormones were determined by ELISA methods. Moreover, in order to measure the gene expression of the lactogenic hormone's receptors in the mammary gland a real time - reverse transcription polymerase chain reaction (RT-PCR) method was performed. The results showed that ethyl acetate fraction of torbangun leaves (EA) (a) was not significantly stimulating the synthesis of serum prolactin and estradiol at day 14 and day 28 lactation period, (b) down-regulated the gene expression of estradiol receptor (ERα) at day 28, and (c) up-regulated the gene expression of prolactin receptor (PRLR) in mammary gland at day 14 and day 28. This study indicated that ethyl acetate fraction of torbangun leaves was induced milk production, within up-regulated the gene expression of prolactin receptor (PRLR) in the mammary gland of lactation rats.

Prolactin improves hepatic steatosis via CD36 pathway

Prolactin (PRL) is a multifunctional polypeptide with effects on metabolism, however, little is known about its effect on hepatic steatosis and lipid metabolism. Herein, we aimed to assess the role of PRL in the development of non-alcoholic fatty liver disease (NAFLD). The serum PRL levels of 456 patients with NAFLD, 403 controls without NAFLD diagnosed by ultrasound, and 85 individuals with liver histology obtained during metabolic surgery (44 female and 30 male patients with NAFLD and 11 age-matched non-NAFLD female individuals) were evaluated. The expression of the gene encoding the prolactin receptor (PRLR) and signalling molecules involved in hepatic lipid metabolism were evaluated in human liver and HepG2 cells. The effects of overexpression of PRLR or fatty acid translocase (FAT)/CD36 or knockdown of PRLR on hepatic lipid metabolism were tested in free fatty acid (FFA)-treated HepG2 cells. Circulating PRL levels were lower in individuals with ultrasound-diagnosed NAFLD (men: 7.9 [range, 5.9-10.3] µg/L; women: 8.7 [range, 6.1-12.4] µg/L) than those with non-NAFLD (men: 9.1 [range, 6.8-13.0] µg/L, p = 0.002; women: 11.6 [range, 8.2-16.1] µg/L, p <0.001). PRL levels in patients with biopsy-proven severe hepatic steatosis were lower compared with those with mild-to-moderate hepatic steatosis in both men (8.3 [range, 5.4-9.5] µg/L vs. 9.7 [range, 7.1-12.3] µg/L, p = 0.031) and women (8.5 [range, 4.2-10.6] µg/L vs. 9.8 [range, 8.2-15.7] µg/L, p = 0.027). Furthermore, hepatic PRLR gene expression was significantly reduced in patients with NAFLD and negatively correlated with CD36 gene expression. In FFA-induced HepG2 cells, PRL treatment or PRLR overexpression significantly reduced the expression of CD36 and lipid content, effects that were abrogated after silencing of PRLR. Furthermore, overexpression of CD36 significantly reduced the PRL-mediated improvement in lipid content. Our results reveal a novel association between the central nervous system and the liver, whereby PRL/PRLR improved hepatic lipid accumulation via the CD36 pathway. Our clinical study suggests a negative association between prolactin (PRL)/prolactin receptor (PRLR) and the presence of non-alcoholic fatty liver disease (NAFLD). Using cell experiments, we found that PRL ameliorates hepatic steatosis via the hepatic PRLR and fatty acid translocase (FAT)/CD36, a key transporter of free fatty acid uptake in liver. Our findings suggest a novel approach to improving NAFLD using PRL and PRLR. Clinical trial number: NCT03296605.

Role of EGF/ERBB1 in the transcriptional regulation of the prolactin receptor independent of estrogen and prolactin in breast cancer cells.

Prolactin receptor (PRLR) and epidermal growth factor receptor (EGFR/ERBB1) have important roles in the physiology of the human breast and in the etiology and progression of breast cancer. Our present studies in MCF-7 cells revealed that EGF induces up-regulation of PRLR via activation of EGFR signalling pathways leading to activation of estrogen receptor α (ERα). EGF treatment of MCF-7 cells cultured in absence of estradiol induced expression of PRLR that was consistent with the activation of PRLR generic promoter (hPIII). These were abolished by ERα antagonist and siRNA, indicating involvement of ERα in EGF-induced hPIII promoter activity. MEK/MAPK and PI3K/AKT pathways participate in the phosphorylation of ERα induced by EGF/EGFR. PI3K and MEK inhibitors abolished EGF-induced PRLR promoter activity. Increased recruitment of non-DNA bound unliganded ERα to Sp1 and C/EBPβ bound to their sites at hPIII induced by EGF was abrogated by ERα siRNA demonstrating the requisite role of phospho-ERα in PRLR upregulation. EGF/EGFR, independent of endogenous prolactin induced phosphorylation of STAT5b with participation of c-SRC and recruitment of STAT5b:STAT5b to a GAS site at hPIII. STAT5b interaction with ERα was essential for stable phospho-ERα recruitment to the SP1/CEBPβ complex. These studies indicate a role for paracrine EGF via EGFR independent of estrogen and prolactin in the transcriptional activation of PRLR gene expression and its contribution to high levels of PRLRs in breast cancer. These by maximizing the actions of endogenous prolactin could have a role in cancer progression and resistance to endocrine therapy.

The Prolactin Receptor Gene Expression Variance in Marshes and Riverine Buffalos in Iraq

The Prolactin Receptor Gene Expression Variance in Marshes and Riverine Buffalos in Iraq

Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy

Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro-differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation.

Endocrine control of canine mammary neoplasms: serum reproductive hormone levels and tissue expression of steroid hormone, prolactin and growth hormone receptors.

BackgroundNeoplasms of the mammary gland are among the most common diseases in female domestic dogs (Canis familiaris). It is assumed that reproductive hormones influence tumorigenesis in this species, although the precise role of the endocrine milieu and reproductive state is subject to continuing discussion. In line with this, a recent systematic review of available data on the development of mammary neoplasms revealed weak evidence for risk reduction after neutering and an effect of age at neutering. Investigation of several hormone receptors has revealed decreased expression of estrogen receptor-alpha (ERα, ESR1), progesterone (P4) receptor (PGR), prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) associated with neoplastic differentiation of mammary tissues. In other studies, increased levels of estrogens, progesterone and prolactin were found in serum and/or tissue homogenates of dogs with malignant neoplasms. However, the association between these entities within one animal population was never previously examined. Therefore, this study investigated the association between circulating serum concentrations of estradiol-17β, progesterone and prolactin, and gene expression of ERα (ESR1), ERβ (ESR2), PGR, PRLR, PRL and GHR, with respect to reproductive state (spayed vs. intact) and cycle stage (anestrus vs. diestrus). Additionally, the expression of E-cadherin (CDH-1) was evaluated as a possible indicator of metastatic potential.ResultsFor all receptors, the lowest gene expression was found in malignant tumors compared to normal tissues of affected dogs. Steroid levels were not influenced by their corresponding receptor expression in mammary neoplasms, but increased PRL levels were negatively associated with low PRLR gene expression in malignant tumors. The expression of CDH-1 was influenced by tumor malignancy and cycle stage, i.e., the highest gene expression was found in benign mammary tumors in diestrous dogs compared to normal and malignant mammary tissues of anestrous and spayed dogs.ConclusionsHerein, it has been confirmed that transformation towards malignant neoplasms is associated with significant reduction of gene expression of particular hormone receptors. Only PRLR in malignant tumors seems to be influenced by circulating PRL levels. In dogs, CDH-1 can be used as a prognostic factor; its expression, however, in benign tumors is influenced by cycle stage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0546-y) contains supplementary material, which is available to authorized users.

Coexisting Prolactinoma and Primary Aldosteronism: Is There a Pathophysiological Link?

Coexisting prolactinoma-primary aldosteronism (PA) is infrequently reported. The objective of the study was to identify patients with prolactinoma-PA and test the hypothesis that elevated prolactin (PRL) concentrations play a role in PA pathogenesis. Hyperprolactinemia/prolactinoma was diagnosed in PA patients from two referral centers (Munich, Germany, and Turin, Italy) and in essential hypertensive (EH) patients from one center (Turin). PRL receptor (PRLR) gene expression was determined by microarrays on aldosterone-producing adenomas and normal adrenals and validated by real-time PCR. H295R adrenal cells were incubated with 100 nM PRL, and gene expression levels were determined by real-time PCR and aldosterone production was quantified. Seven patients with prolactinoma-PA were identified: four of 584 and three of 442 patients from the Munich and Turin PA cohorts, respectively. A disproportionate number presented with macroprolactinomas (five of seven). There were five cases of hyperprolactinemia with no cases of macroprolactinoma of 14 790 patients in a general EH cohort. In a population of PA patients case-control matched 1:3 with EH patients there were two cases of hyperprolactinemia of 270 PA patients and no cases in the EH cohort (n = 810). PRLR gene expression was significantly up-regulated in the aldosterone-producing adenomas compared with normal adrenals (1.7-fold and 1.5-fold by microarray and real-time PCR, respectively). In H295R cells, PRL treatment resulted in 1.3-fold increases in CYP11B2 expression and aldosterone production. Elevated PRL caused by systemic hyperprolactinemia may contribute to the development of PA in those cases in which the two entities coexist.

Evaporative cooling in late-gestation Murrah buffaloes potentiates immunity around transition period and overcomes reproductive disorders

The objective of the study was to observe the effect of evaporative cooling during late gestation on immunity around the transition period and the probable outcome on reproductive disorders in Murrah buffaloes. Sixteen pregnant dry Murrah buffaloes at 60 days prepartum were selected and divided into two groups of eight animals each. Group 1 buffaloes remained without the provision of cooling, whereas the second group of buffaloes was managed under fans and mist cooling during the dry period. After parturition, all the animals were managed under evaporative cooling. Dry matter intake was significantly (P < 0.05) higher in cooled relative to noncooled animals at −15, 0, and +20 days of parturition. Cortisol and prolactin levels were significantly (P < 0.05) higher in noncooled relative to cooled animals at −15 and 0 days of parturition. However, prolactin was significantly (P < 0.05) higher in cooled animals at +20 days. Messenger RNA expression of prolactin receptor gene (PRL-R) was upregulated and suppressor of cytokine signaling gene 1 (SOCS-1) was downregulated in cooled animals at −20, 0, and +20 days of parturition. Tumor necrosis factor α and interleukin 4 levels remained significantly (P < 0.05) higher in cooled animals at −20, 0, and +20 days of parturition. Interleukin 6 was significantly (P < 0.05) lower in cooled animals at −20 and 0 days. Interferon γ levels were significantly higher at −20 and +20 days of parturition in cooled relative to noncooled animals. The reproductive disorders such as retention of placenta, metritis, and endometritis occurred at the rate of 37.25%, 25%, and 12.25% in the noncooled group, whereas only retention of placenta was observed in the cooled (12.5%) group.

MRNA expression of prolactin receptor in sheep pituitary and its effect on maternal behavior.

Prolactin receptor (PRLR) is the specific receptor for prolactin. Brain-specific control of PRLR gene expression is correlated with the induction of maternal behavior. The aim of this study was to investigate the dynamic changes in the PRLR mRNA level in the sheep pituitary gland and its effect on ewe maternal behavior. The mRNA expression of PRLR during non-pregnancy stage was maintained at low but detectable levels, as was the case during mid-gestation. After that, expression began increasing and reached a maximum during the early postpartum followed by a gradual decline during the mid-postpartum and late postpartum stages. A trend of higher PRLR mRNA expression was observed during the postpartum stage relative to the non-pregnancy and pregnancy stages. Expression of PRLR mRNA was significantly higher in the normal maternal behavior group than that in the abnormal maternal behavior group. There may be a correlation between PRLR mRNA expression and ewe maternal behavior, especially in early postpartum.