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Journal of Mammary Gland Biology and... Mar 2008There is increasing evidence that prolactin (PRL) and growth hormone (GH) act as growth-promoters of breast tumors. Recent arguments have accumulated to suggest that... (Review)
Review
There is increasing evidence that prolactin (PRL) and growth hormone (GH) act as growth-promoters of breast tumors. Recent arguments have accumulated to suggest that when they are locally-produced within the mammary tissue, these hormones, acting by an autocrine-paracrine mechanism may have enhanced, or even specific functions compared to endocrine PRL and GH. Classical drugs blocking pituitary hormone production (dopamine and somatostatin analogs) are ineffective on extrapituitary expression of PRL/GH genes, therefore the undesirable effects of these locally-produced hormones remain a target of interest for alternative strategies. This has encouraged the development of competitive PRL and/or GH receptor antagonists, which involve engineered variants of natural receptor ligands (PRL or GH) aimed at blocking receptor activation rather than hormone production in peripheral tissues. This article overviews the rational design of this new class of molecules, their specific molecular features (receptor specificity, biological properties, etc.) and whenever available, the data that have been obtained in cell or animal models of breast cancer.
Topics: Animals; Binding Sites; Drug Design; Humans; Mutation; Prolactin; Receptors, Prolactin; Receptors, Somatotropin
PubMed: 18219565
DOI: 10.1007/s10911-008-9066-8 -
Annals of the New York Academy of... May 1998Prolactin (PRL), secreted by the pituitary, decidua, and lymphoid cells, has been shown to have a regulatory role in reproduction, immune function, and cell growth in... (Review)
Review
Prolactin (PRL), secreted by the pituitary, decidua, and lymphoid cells, has been shown to have a regulatory role in reproduction, immune function, and cell growth in mammals. The effects of PRL are mediated by a membrane-bound receptor that is a member of the superfamily of cytokine receptors. Formation of a trimer, consisting of one molecule of ligand and two molecules of receptor, appears to be a necessary prerequisite for biological activity. The function of these receptors is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases (JAKs) and signal transducers and activators of transcription (STATs). To study these receptors, we have used two approaches: mutational analysis of their cytoplasmic domains coupled with functional tests and inactivation (knockout) of the receptor gene by homologous recombination in mice. We have produced mice by gene targeting in embryonic stem cells carrying a germline null mutation of the prolactin receptor gene. Heterozygous (+/-) females show almost complete failure to lactate, following their first, but not subsequent pregnancies. Homozygous (-/-) females are infertile as a result of multiple reproductive abnormalities, including ovulation of premiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Half of the homozygous males are infertile or show reduced fertility. In view of the wide-spread distribution of PRL receptors, other phenotypes including those on the immune system, are currently being evaluated in -/- animals. This study establishes the prolactin receptor as a key regulator of mammalian reproduction and provides the first total ablation model to further study the role of the prolactin receptor and its ligands.
Topics: Animals; Immune System; Mice; Mice, Knockout; Neurosecretory Systems; Prolactin; Receptors, Prolactin; Signal Transduction; T-Lymphocytes
PubMed: 9629276
DOI: 10.1111/j.1749-6632.1998.tb09588.x -
Molecular and Cellular Endocrinology Feb 1993
Review
Topics: Animals; Breast; Female; Gene Expression; Homeostasis; Hormones; Humans; Mammary Glands, Animal; Receptors, Prolactin
PubMed: 8472840
DOI: 10.1016/0303-7207(93)90247-h -
Endocrinology Dec 1996To determine the role of the hormone prolactin and its receptor on the differentiation, growth, and metabolic activity of cells of bone marrow origin, prolactin receptor...
To determine the role of the hormone prolactin and its receptor on the differentiation, growth, and metabolic activity of cells of bone marrow origin, prolactin receptor expression was assessed in bone marrow stromal cells. Using reverse transcription - polymerase chain reaction, BMS2 cells, a bone marrow stromal cell line, were shown to express prolactin receptors following adipocyte differentiation, using three different adipocyte-differentiation protocols. Primary bone marrow stromal cells also show a dose-dependent increase in prolactin receptor expression following treatment with adipogenic agonists. That prolactin receptor expression is inducible upon adipocyte differentiation was confirmed using a preadipocyte cell line 3T3 - L1. Further, prolactin receptor parallels lipoprotein lipase gene expression in 3T3-L1 cells. These results suggest that prolactin and its receptor may play a role in differentiation and/or metabolism of pre-adipocytes and adipocytes.
Topics: Adipocytes; Animals; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Mice; Pioglitazone; Receptors, Prolactin; Rosiglitazone; Stem Cells; Stromal Cells; Thiazoles; Thiazolidinediones
PubMed: 8940406
DOI: 10.1210/endo.137.12.8940406 -
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 -
Biochimica Et Biophysica Acta Jul 2014Long-form (LF) homodimers of the human prolactin receptor (PRLR) mediate prolactin's diverse actions. Short form S1b inhibits the LF function through heterodimerization....
Impact of subdomain D1 of the short form S1b of the human prolactin receptor on its inhibitory action on the function of the long form of the receptor induced by prolactin.
BACKGROUND
Long-form (LF) homodimers of the human prolactin receptor (PRLR) mediate prolactin's diverse actions. Short form S1b inhibits the LF function through heterodimerization. Reduced S1b/LF-ratio in breast cancer could contribute to tumor development/progression. Current work defines the structural and functional relevance of the D1 domain of S1b on its inhibitory function on prolactin-induced LF function.
METHODS
Studies were conducted using mutagenesis, promoter/signaling analyses, bioluminescence resonance energy transfer (BRET) and molecular modeling approaches.
RESULTS
Mutation of E69 in D1 S1b or adjacent residues at the receptor surface near to the binding pocket (S) causes loss of its inhibitory effect while mutations away from this region (A) or in the D2 domain display inhibitory action as the wild-type. All S1b mutants preserved prolactin-induced Jak2 activation. BRET reveals an increased affinity in D1 mutated S1b (S) homodimers in transfected cells stably expressing LF. In contrast, affinity in S1b homodimers with either D1 (A) or D2 mutations remained unchanged. This favors LF mediated signaling induced by prolactin. Molecular dynamics simulations show that mutations (S) elicit major conformational changes that propagate downward to the D1/D2 interface and change their relative orientation in the dimers.
CONCLUSIONS
These findings demonstrate the essential role of D1 on the S1b structure and its inhibitory action on prolactin-induced LF-mediated function.
GENERAL SIGNIFICANCE
Major changes in receptor conformation and dimerization affinity are triggered by single mutations in critical regions of D1. Our structure-function/simulation studies provide a basis for modeling and design of small molecules to enhance inhibition of LF activation for potential use in breast cancer treatment.
Topics: Breast Neoplasms; Cell Line; Dimerization; Female; HEK293 Cells; Humans; Janus Kinase 2; Mutation; Prolactin; Promoter Regions, Genetic; Protein Binding; Protein Conformation; Protein Isoforms; Protein Structure, Tertiary; Receptors, Prolactin; Signal Transduction; Structure-Activity Relationship
PubMed: 24735798
DOI: 10.1016/j.bbagen.2014.04.006 -
Journal of Theoretical Biology May 2005A mathematical model of prolactin regulating its own receptors was developed, and compared with experimental data on a qualitative level. The model incorporates the...
A mathematical model of prolactin regulating its own receptors was developed, and compared with experimental data on a qualitative level. The model incorporates the kinetics of prolactin-receptor interactions and subsequent signalling by prolactin-receptor dimers to regulate the production of receptor mRNA and hence the receptor population. The model relates changes in plasma prolactin concentration to prolactin receptor (PRLR) gene expression, and can be used for predictive purposes. The cell signalling that leads to the activation of target genes, and the mechanisms for regulation of transcription, were treated empirically in the model. The model's parameters were adjusted so that model simulations agreed with experimentally observed responses to administration of prolactin in sheep. In particular, the model correctly predicts insensitivity of receptor mRNA regulation to a series of subcutaneous injections of prolactin, versus sensitivity to prolonged infusion of prolactin. In the latter case, response was an acute down-regulation followed by a prolonged up-regulation of mRNA, with the magnitude of the up-regulation increasing with the duration of infusion period. The model demonstrates the feasibility of predicting the in vivo response of prolactin target genes to external manipulation of plasma prolactin, and could provide a useful tool for identifying optimal prolactin treatments for desirable outcomes.
Topics: Animals; Gene Expression Regulation; Infusions, Intravenous; Injections, Subcutaneous; Models, Biological; Prolactin; RNA, Messenger; Receptors, Prolactin; Sheep; Signal Transduction; Skin
PubMed: 15757685
DOI: 10.1016/j.jtbi.2004.11.025 -
Cancer Research Apr 2017Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack...
Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of ovarian cancers express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into ovarian cancer cells via PRLR-mediated endocytosis. Compared with current clinical MRI techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant ovarian cancer. These features endow PRLR-targeted imaging with the potential to transform ovarian cancer detection. .
Topics: Animals; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Endocytosis; Female; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Mice; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Placental Lactogen; Prolactin; Receptors, Prolactin; Sensitivity and Specificity; Tissue Array Analysis
PubMed: 28202518
DOI: 10.1158/0008-5472.CAN-16-1454 -
Progress in Brain Research 2001The vital role played by prolactin during pregnancy and lactation is emphasized by the physiological adaptations that occur in the mother to maintain a prolonged state... (Review)
Review
The vital role played by prolactin during pregnancy and lactation is emphasized by the physiological adaptations that occur in the mother to maintain a prolonged state of hyperprolactinemia. In many species the placenta provides a source of lactogenic hormones in the circulation, ensuring the continued presence of a hormone capable of activating the prolactin receptor throughout pregnancy. In addition, the tuberoinfundibular dopamine neurons, which normally maintain a tonic inhibitory influence over prolactin secretion, show a reduced ability to respond to prolactin during late pregnancy and lactation, allowing high levels of prolactin to be maintained unopposed by a regulatory feedback mechanisms. There is clear evidence that systemic prolactin gains access to the cerebrospinal fluid, from where it can diffuse to numerous brain regions. Prolactin receptors are expressed in several hypothalamic nuclei, including the medial preoptic and arcuate nuclei, and we have observed marked increases in expression of prolactin receptors in these nuclei during lactation. Moreover, a number of hypothalamic nuclei, including the paraventricular, supraoptic and ventromedial nuclei, in which prolactin receptors were not detected in diestrous rats, were found to express significant amounts of prolactin receptor during lactation. These observations have important implications for the variety of documented actions of prolactin on the brain. Prolactin has been reported to influence numerous brain functions, including maternal behavior, feeding and appetite, oxytocin secretion, and ACTH secretion in response to stress. In light of the high circulating levels of prolactin during pregnancy and lactation and the increased expression of prolactin receptors in the hypothalamus, many of these effects of prolactin may be enhanced or exaggerated during lactation. Hence, prolactin may be a key player in the coordination of neuroendocrine and behavioral adaptations of the maternal brain.
Topics: Animals; Brain; Female; Humans; Hypothalamus; Lactation; Pregnancy; Pregnancy, Animal; Prolactin; Receptors, Prolactin
PubMed: 11589128
DOI: 10.1016/s0079-6123(01)33012-1 -
Frontiers in Endocrinology 2021Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy,... (Review)
Review
Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy, cell growth, and differentiation. However, PRL is nowadays known to have a strong implication in oncogenic processes, making it essential to delve into the mechanisms governing these actions. PRL and its receptor (PRLR) activate a series of effects such as survival, cellular proliferation, migration, invasion, metastasis, and resistance to treatment, being highly relevant in developing certain types of cancer. Because women produce high levels of PRL, its influence in gynecological cancers is herein reviewed. It is interesting that, other than the 23 kDa PRL, whose mechanism of action is endocrine, other variants of PRL have been observed to be produced by tumoral tissue, acting in a paracrine/autocrine manner. Because many components, including PRL, surround the microenvironment, it is interesting to understand the hormone's modulation in cancer cells. This work aims to review the most important findings regarding the PRL/PRLR axis in cervical, ovarian, and endometrial cancers and its molecular mechanisms to support carcinogenesis.
Topics: Cell Transformation, Neoplastic; Female; Genital Neoplasms, Female; Humans; Prolactin; Receptors, Prolactin; Signal Transduction; Tumor Microenvironment
PubMed: 34745013
DOI: 10.3389/fendo.2021.747810