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Journal of Molecular Endocrinology Apr 2023The prolactin receptor (PRLR) signals predominantly through the JAK2-STAT5 pathway regulating multiple physiological functions relating to fertility, lactation, and...
The prolactin receptor (PRLR) signals predominantly through the JAK2-STAT5 pathway regulating multiple physiological functions relating to fertility, lactation, and metabolism. However, the molecular pathology and role of PRLR mutations and signalling are incompletely defined, with progress hampered by a lack of reported disease-associated PRLR variants. To date, two common germline PRLR variants are reported to demonstrate constitutive activity, with one, Ile146Leu, overrepresented in benign breast disease, while a rare activating variant, Asn492Ile, is reported to be associated with an increased incidence of prolactinoma. In contrast, an inactivating germline heterozygous PRLR variant (His188Arg) was reported in a kindred with hyperprolactinaemia, while an inactivating compound heterozygous PRLR variant (Pro269Leu/Arg171Stop) was identified in an individual with hyperprolactinaemia and agalactia. We hypothesised that additional rare germline PRLR variants, identified from large-scale sequencing projects (ExAC and GnomAD), may be associated with altered in vitro PRLR signalling activity. We therefore evaluated >300 previously uncharacterised non-synonymous, germline PRLR variants and selected 10 variants for in vitro analysis based on protein prediction algorithms, proximity to known functional domains and structural modelling. Five variants, including extracellular and intracellular domain variants, were associated with altered responses when compared to the wild-type receptor. These altered responses included loss- and gain-of-function activities related to STAT5 signalling, Akt and FOXO1 activity, as well as cell viability and apoptosis. These studies provide further insight into PRLR structure-function and indicate that rare germline PRLR variants may have diverse modulating effects on PRLR signalling, although the pathophysiologic relevance of such alterations remains to be defined.
Topics: Female; Humans; Receptors, Prolactin; STAT5 Transcription Factor; Hyperprolactinemia; Signal Transduction; Prolactin; Carrier Proteins
PubMed: 36445946
DOI: 10.1530/JME-22-0164 -
Biochemistry. Biokhimiia Apr 2019The review describes functional and structural features of different isoforms of prolactin receptor, mechanisms of signaling pathway activation, and molecular messengers... (Review)
Review
The review describes functional and structural features of different isoforms of prolactin receptor, mechanisms of signaling pathway activation, and molecular messengers involved in the transmission and termination of signal from the prolactin receptor isoforms. Changes in the ratio between prolactin receptor isoforms, key mediators of prolactin signal transduction and termination in various organs and tissues, are analyzed. Special attention is given to the role of molecular mediators and the ratio between the isoforms in normal physiological functions and pathologies. Approaches for therapeutic correction of prolactin signaling impairments are discussed.
Topics: Animals; Humans; Neoplasms; Prolactin; Protein Inhibitors of Activated STAT; Protein Isoforms; Receptors, Prolactin; STAT Transcription Factors; Signal Transduction; Suppressor of Cytokine Signaling Proteins
PubMed: 31228925
DOI: 10.1134/S0006297919040011 -
Biochimica Et Biophysica Acta. Reviews... May 2023Breast cancer (BC) is the leading cause of cancer death in women. This disease is heterogeneous, with clinical subtypes being estrogen receptor-α (ER-α) positive,... (Review)
Review
Breast cancer (BC) is the leading cause of cancer death in women. This disease is heterogeneous, with clinical subtypes being estrogen receptor-α (ER-α) positive, having human epidermal growth factor receptor 2 (HER2) overexpression, or being triple-negative for ER-α, progesterone receptor, and HER2 (TNBC). The ER-α positive and HER2 overexpressing tumors can be treated with agents targeting these proteins, including tamoxifen and pertuzumab, respectively. Despite these treatments, resistance and metastasis are problematic, while TNBC is challenging to treat due to the lack of suitable targets. Many studies examining BC and other tumors indicate a role for N-myc downstream-regulated gene-1 (NDRG1) as a metastasis suppressor. The ability of NDRG1 to inhibit metastasis is due, in part, to the inhibition of the initial step in metastasis, namely the epithelial-to-mesenchymal transition. Paradoxically, there are also reports of NDRG1 playing a pro-oncogenic role in BC pathogenesis. The oncogenic effects of NDRG1 in BC have been reported to relate to lipid metabolism or the mTOR signaling pathway. The molecular mechanism(s) of how NDRG1 regulates the activity of multiple signaling pathways remains unclear. Therapeutic strategies that up-regulate NDRG1 have been developed and include agents of the di-2-pyridylketone thiosemicarbazone class. These compounds target oncogenic drivers in BC cells, suppressing the expression of multiple key hormone receptors including ER-α, progesterone receptor, androgen receptor, and prolactin receptor, and can also overcome tamoxifen resistance. Considering the varying role of NDRG1 in BC pathogenesis, further studies are required to examine what subset of BC patients would benefit from pharmacopeia that up-regulate NDRG1.
Topics: Humans; Female; Cell Cycle Proteins; Intracellular Signaling Peptides and Proteins; Receptors, Progesterone; Triple Negative Breast Neoplasms; Cell Line, Tumor; Tamoxifen
PubMed: 36841367
DOI: 10.1016/j.bbcan.2023.188871 -
Advances in Experimental Medicine and... 2015Prolactin (PRL) is a peptide hormone produced by the pituitary gland and diverse extrapituitary sites, which triggers activation of various signaling pathways after... (Review)
Review
Prolactin (PRL) is a peptide hormone produced by the pituitary gland and diverse extrapituitary sites, which triggers activation of various signaling pathways after binding to its receptor (PRLr) resulting in the activation of specific genes associated with the pleiotropic activities of PLR. To date, various PRLr isoforms have been described, generated by post-transcriptional or post-translational processes. PRL has been associated with the modulation of a variety of actions in the immune response and inflammatory processes in several physiologic and pathologic conditions. However, PRL can have opposite effects, which might be regulated by interaction with the various isoforms of PRLR and PRL variants, as well as the cellular and molecular microenvironment influence.
Topics: Animals; Humans; Immune System; Inflammation; Myeloid Cells; Neuroimmunomodulation; Neurosecretory Systems; Prolactin; Receptors, Prolactin
PubMed: 25472542
DOI: 10.1007/978-3-319-12114-7_11 -
Molecular Pharmaceutics Jun 2018Antibodies labeled with positron-emitting isotopes have been used for tumor detection, predicting which patients may respond to tumor antigen-directed therapy, and...
Antibodies labeled with positron-emitting isotopes have been used for tumor detection, predicting which patients may respond to tumor antigen-directed therapy, and assessing pharmacodynamic effects of drug interventions. Prolactin receptor (PRLR) is overexpressed in breast and prostate cancers and is a new target for cancer therapy. We evaluated REGN2878, an anti-PRLR monoclonal antibody, as an immunoPET reagent. REGN2878 was labeled with Zr-89 after conjugation with desferrioxamine B or labeled with I-131/I-124. In vitro determination of the half-maximal inhibitory concentration (IC50) of parental REGN2878, DFO-REGN2878, and iodinated REGN2878 was performed by examining the effect of the increasing amounts of these on uptake of trace-labeled I-131 REGN2878. REGN1932, a non-PRLR binding antibody, was used as a control. Imaging and biodistribution studies were performed in mice bearing tumor xenografts with various expression levels of PRLR, including MCF-7, transfected MCF-7/PRLR, PC3, and transfected PC3/PRLR and T4D7v11 cell lines. The specificity of uptake in tumors was evaluated by comparing Zr-89 REGN2878 and REGN1932, and in vivo competition compared Zr-89 REGN2878 uptake in tumor xenografts with and without prior injection of 2 mg of nonradioactive REGN2878. The competition binding assay of DFO-REGN2878 at ratios of 3.53-5.77 DFO per antibody showed IC50 values of 0.4917 and 0.7136 nM, respectively, compared to 0.3455 nM for parental REGN2878 and 0.3343 nM for I-124 REGN2878. Imaging and biodistribution studies showed excellent targeting of Zr-89 REGN2878 in PRLR-positive xenografts at delayed times of 189 h (presented as mean ± 1 SD, percent injected activity per mL (%IA/mL) 74.6 ± 33.8%IA/mL). In contrast, MCF-7/PRLR tumor xenografts showed a low uptake (7.0 ± 2.3%IA/mL) of control Zr-89 REGN1932 and a very low uptake and rapid clearance of I-124 REGN2878 (1.4 ± 0.6%IA/mL). Zr-89 REGN2878 has excellent antigen-specific targeting in various PRLR tumor xenograft models. We estimated, using image-based kinetic modeling, that PRLR antigen has a very rapid in vivo turnover half-life of ∼14 min from the cell membrane. Despite relatively modest estimated tumor PRLR expression numbers, PRLR-expressing cells have shown final retention of the Zr-89 REGN2878 antibody, with an uptake that appeared to be related to PRLR expression. This reagent has the potential to be used in clinical trials targeting PRLR.
Topics: Animals; Antibodies, Monoclonal; Cell Line, Tumor; Female; Humans; Immunoconjugates; Mice; Mice, Nude; Molecular Imaging; Neoplasms; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Prolactin; Tissue Distribution; Xenograft Model Antitumor Assays
PubMed: 29684277
DOI: 10.1021/acs.molpharmaceut.7b01133 -
Journal of Neuroendocrinology Nov 2020Prolactin is named after its vital role of promoting milk production during lactation, although it has been implicated in multiple functions within the body, including... (Review)
Review
Prolactin is named after its vital role of promoting milk production during lactation, although it has been implicated in multiple functions within the body, including metabolism and energy homeostasis. Prolactin has been hypothesised to play a key role in driving many of the adaptations of the maternal body to allow the mother to meet the physiological demands of both pregnancy and lactation, including the high energetic demands of the growing foetus followed by milk production to support the offspring after birth. Prolactin receptors are found in many tissues involved in metabolism and food intake, such as the pancreas, liver, hypothalamus, small intestine and adipose tissue. We review the literature examining the effects of prolactin in these various tissues and how they relate to changes in function in physiological states of high prolactin, such as pregnancy and lactation, and in pathological states of hyperprolactinaemia in the adult. In many cases, whether prolactin promotes healthy metabolism or leads to dysregulation of metabolic functions is highly dependent on the situation. Overall, although prolactin may not play a major role in regulating metabolism and body weight outside of pregnancy and lactation, it definitely has the ability to contribute to metabolic function.
Topics: Animals; Female; Humans; Lactation; Metabolism; Pregnancy; Prolactin; Receptors, Prolactin
PubMed: 33463813
DOI: 10.1111/jne.12888 -
Archives of Endocrinology and Metabolism 2016Prolactin is best known for its effects of stimulating mammary gland development and lactogenesis. However, prolactin is a pleiotropic hormone that is able to affect... (Review)
Review
Prolactin is best known for its effects of stimulating mammary gland development and lactogenesis. However, prolactin is a pleiotropic hormone that is able to affect several physiological functions, including fertility. Prolactin receptors (PRLRs) are widely expressed in several tissues, including several brain regions and reproductive tract organs. Upon activation, PRLRs may exert prolactin's functions through several signaling pathways, although the recruitment of the signal transducer and activator of transcription 5 causes most of the known effects of prolactin. Pathological hyperprolactinemia is mainly due to the presence of a prolactinoma or pharmacological effects induced by drugs that interact with the dopamine system. Notably, hyperprolactinemia is a frequent cause of reproductive dysfunction and may lead to infertility in males and females. Recently, several studies have indicated that prolactin may modulate the reproductive axis by acting on specific populations of hypothalamic neurons that express the Kiss1 gene. The Kiss1 gene encodes neuropeptides known as kisspeptins, which are powerful activators of gonadotropin-releasing hormone neurons. In the present review, we will summarize the current knowledge about prolactin's actions on reproduction. Among other aspects, we will discuss whether the interaction between prolactin and the Kiss1-expressing neurons can affect reproduction and how kisspeptins may become a novel therapeutic approach to treat prolactin-induced infertility.
Topics: Female; Humans; Hyperprolactinemia; Hypothalamus; Infertility; Kisspeptins; Male; Prolactin; Receptors, Prolactin; Reproduction; Sex Factors; Signal Transduction
PubMed: 27901187
DOI: 10.1590/2359-3997000000230 -
Neuroendocrinology 2022Converging evidence indicates prolactin (PRL) and diabetes play an important role in the pathophysiology of cognitive impairment. However, little is known about the... (Review)
Review
BACKGROUND
Converging evidence indicates prolactin (PRL) and diabetes play an important role in the pathophysiology of cognitive impairment. However, little is known about the mechanisms responsible for the effects of PRL and diabetes on cognitive impairment.
SUMMARY
We summarize and review the available literature and current knowledge of the association between PRL and diabetes on aspects of cognitive impairment.
KEY MESSAGES
The phosphatidylinositol 3-kinase/protein kinase B pathway is central to the molecular mechanisms underlying how PRL and diabetes interact in cognitive impairment. Further work is needed to identify the interaction between PRL and diabetes, especially in the molecular aspects of cognitive impairment, which can suggest novel strategies for cognitive dysfunction treatment.
Topics: Cognitive Dysfunction; Diabetes Mellitus; Humans; Prolactin; Receptors, Prolactin
PubMed: 34963126
DOI: 10.1159/000521653 -
Pharmacology & Therapeutics Nov 2017In the era of precision medicine, the identification of new targets is a constant challenge to improve cancer therapy. Preclinical investigations, epidemiological... (Review)
Review
In the era of precision medicine, the identification of new targets is a constant challenge to improve cancer therapy. Preclinical investigations, epidemiological studies and analyses of tissue specimens from patients strongly support the contribution of prolactin receptor (PRLR) signaling to breast and prostate tumorigenesis and cancer progression. Although a clear causative link with mutations of the genes encoding prolactin or its receptor is lacking, increased PRLR signaling in these cancers can be assessed by the overexpression of cognate proteins and is often confirmed by over-activation of downstream signaling effectors. Nevertheless, the PRLR neutralizing antibody LFA102 tested recently in a Phase I trial in advanced, PRLR-positive prostate cancer and breast cancer patients failed to provide any clinical benefit. This underlines the need to better understand the actual impact of PRLR signaling on the progression of these cancers. Canonical PRLR-triggered signaling cascades include STAT5A/B, ERK1/2, PI3K/Akt, FAK and Src family kinases. Recent studies suggested that the nature and the outcome of PRLR signaling might be markedly different in breast than in prostate cancer. In the latter, like in many organs, PRLR/STAT5 signaling acts as a pro-tumorigenic pathway. In particular, it promotes the amplification of treatment-resistant prostate stem/progenitor cells, predicts early cancer recurrence and favors metastatic dissemination. In contrast, PRLR/STAT5 signaling was recently proposed to prevent breast cancer cell dissemination and to predict favorable clinical outcomes. While there is no evidence that pathways other than STAT5 are activated by prolactin in the prostate, these alternate signaling cascades may be primarily responsible for the pro-tumorigenic effects of prolactin in breast cancer. If these conclusions are confirmed in future studies, the therapeutic targeting of PRLR signaling in breast and prostate cancer may warrant the development of organ-specific strategies.
Topics: Animals; Breast Neoplasms; Female; Humans; Male; Prolactin; Prostatic Neoplasms; Receptors, Prolactin; Signal Transduction
PubMed: 28549597
DOI: 10.1016/j.pharmthera.2017.05.009 -
Frontiers in Neuroscience 2020The hypothalamo-pituitary system developed in early vertebrates. Prolactin is an ancient vertebrate hormone released from the pituitary that exerts particularly diverse... (Review)
Review
The hypothalamo-pituitary system developed in early vertebrates. Prolactin is an ancient vertebrate hormone released from the pituitary that exerts particularly diverse functions. The purpose of the review is to take a comparative approach in the description of prolactin, its secretion from pituitary lactotrophs, and hormonal functions. Since the reproductive and osmoregulatory roles of prolactin are best established in a variety of species, these functions are the primary subjects of discussion. Different types of prolactin and prolactin receptors developed during vertebrate evolution, which will be described in this review. The signal transduction of prolactin receptors is well conserved among vertebrates enabling us to describe the whole subphylum. Then, the review focuses on the regulation of prolactin release in mammals as we have the most knowledge on this class of vertebrates. Prolactin secretion in response to different reproductive stimuli, such as estrogen-induced release, mating, pregnancy and suckling is detailed. Reproduction in birds is different from that in mammals in several aspects. Prolactin is released during incubation in avian species whose regulation and functional significance are discussed. Little information is available on prolactin in reptiles and amphibians; therefore, they are mentioned only in specific cases to explain certain evolutionary aspects. In turn, the osmoregulatory function of prolactin is well established in fish. The different types of pituitary prolactin in fish play particularly important roles in the adaptation of eutherian species to fresh water environments. To achieve this function, prolactin is released from lactotrophs in hyposmolarity, as they are directly osmosensitive in fish. In turn, the released prolactin acts on branchial epithelia, especially ionocytes of the gill to retain salt and excrete water. This review will highlight the points where comparative data give new ideas or suggest new approaches for investigation in other taxa.
PubMed: 32612510
DOI: 10.3389/fnins.2020.00621