-
Current Opinion in Obstetrics &... Aug 2019To briefly summarize what is known regarding hyperprolactinemia and prolactin-secreting tumors, and review recent findings. (Review)
Review
PURPOSE OF REVIEW
To briefly summarize what is known regarding hyperprolactinemia and prolactin-secreting tumors, and review recent findings.
RECENT FINDINGS
Prolactin was previously thought to inhibit secretion of gonadotropin-releasing hormone (GnRH) by directly inhibiting the firing of GnRH neurons, resulting in hypogonadotropic hypogonadism and infertility. However, kisspeptin has recently been implicated as the mediator of hyperprolactinemia-induced infertility, by acting upstream of the GnRH neurons as an integrator of endocrine signals.Macroprolactin is generally considered to be inactive and clinically insignificant, but new studies have suggested that patients with macroprolactinemia may have reproductive manifestations as well as sexual dysfunction.Several mutations and polymorphisms in the prolactin receptor have been described, which could describe a genetic cause for prolactinomas and characterize cases of isolated familial hyperprolactinemia.Kisspeptin and tyrosine kinase inhibitors have emerged as potential new therapeutic targets for the treatment of hyperprolactinemia and dopamine-resistant prolactinomas.
SUMMARY
Molecular studies are shedding light on the pathophysiology of hyperprolactinemia and the effects of excess prolactin production on the reproductive system. Similarly, genetic studies have begun to reveal how differences in prolactin receptor function may account for some of the previously 'idiopathic' cases of hyperprolactinemia and bring to light new causes of prolactinomas. Further elucidation of the transcriptional pathways affected by these genetic changes may help to create new therapeutic targets.
Topics: Animals; Female; Genetic Variation; Genomics; Gonadotropin-Releasing Hormone; Humans; Hyperprolactinemia; Infertility; Kisspeptins; Male; Mice; Mice, Transgenic; Neurons; Prolactin; Protein-Tyrosine Kinases; Receptors, Prolactin; Reproduction
PubMed: 31045655
DOI: 10.1097/GCO.0000000000000545 -
Trends in Neurosciences Aug 2020Women experience many pain conditions more frequently when compared with men, but the biological mechanisms underlying sex differences in pain remain poorly understood.... (Review)
Review
Women experience many pain conditions more frequently when compared with men, but the biological mechanisms underlying sex differences in pain remain poorly understood. In particular, little is known about possible sex differences in peripheral nociceptors, the fundamental building blocks of pain transmission. Emerging evidence reveals that prolactin (PRL) signaling at its cognate prolactin receptor (PRLR) in primary afferents promotes nociceptor sensitization and pain in a female-selective fashion. In this review, we summarize recent progress in understanding the female-selective role of PRL/PRLR in nociceptor sensitization and in pathological pain conditions, including postoperative, inflammatory, neuropathic, and migraine pain, as well as opioid-induced hyperalgesia. The clinical implications of the peripheral PRL/PRLR system for the discovery of new therapies for pain control in women are also discussed.
Topics: Female; Humans; Hyperalgesia; Male; Nociceptors; Pain; Prolactin; Receptors, Prolactin
PubMed: 32620290
DOI: 10.1016/j.tins.2020.06.003 -
Frontiers in Endocrinology 2022The hypothalamic neuroendocrine catecholamine dopamine regulates the lactotroph function, including prolactin (PRL) secretion, proliferation, and apoptosis. The... (Review)
Review
The hypothalamic neuroendocrine catecholamine dopamine regulates the lactotroph function, including prolactin (PRL) secretion, proliferation, and apoptosis. The treatment of PRL-secreting tumors, formerly known as prolactinomas, has relied mainly on this physiological characteristic, making dopamine agonists the first therapeutic alternative. Nevertheless, the group of patients that do not respond to this treatment has few therapeutical options. Prolactin is another physiological regulator of lactotroph function, acting as an autocrine/paracrine factor that controls PRL secretion and cellular turnover, inducing apoptosis and decreasing proliferation. Furthermore, the signaling pathways related to these effects, mainly JAK/STAT and PI3K/Akt, and MAPK, have been extensively studied in prolactinomas and other tumors as therapeutic targets. In the present work, the relationship between PRL pathophysiology and prolactinoma development is explored, aiming to comprehend the value of PRL and PRLR-associated pathways as exploratory fields alternative to dopamine-related approaches, which are worth physiological characteristics that might be impaired and can be potentially restored or upregulated to provide more options to the patients.
Topics: Humans; Prolactinoma; Receptors, Prolactin; Dopamine; Prolactin; Pituitary Neoplasms; Phosphatidylinositol 3-Kinases
PubMed: 36714572
DOI: 10.3389/fendo.2022.1057749 -
Oncogenesis Jan 2021Dedifferentiation increased cellular plasticity and stemness are established derivers of tumor heterogeneity, metastasis and therapeutic failure resulting in incurable...
Dedifferentiation increased cellular plasticity and stemness are established derivers of tumor heterogeneity, metastasis and therapeutic failure resulting in incurable cancers. Therefore, it is essential to decipher pro/forward-differentiation mechanisms in cancer that may serve as therapeutic targets. We found that interfering with expression of the receptor for the lactogenic hormone prolactin (PRLR) in breast cancer cells representative of the luminal and epithelial breast cancer subtypes (hormone receptor positive (HR+) and HER2-enriched (HER2-E) resulted in loss of their differentiation state, enriched for stem-like cell subpopulations, and increased their tumorigenic capacity in a subtype-specific manner. Loss of PRLR expression in HR+ breast cancer cells caused their dedifferentiation generating a mesenchymal-basal-like phenotype enriched in CD44+ breast cancer stem-like cells (BCSCs) showing high tumorigenic and metastatic capacities and resistance to anti-hormonal therapy. Whereas loss of PRLR expression in HER2-E breast cancer cells resulted in loss of their luminal differentiation yet enriched for epithelial ALDH+ BCSC population showing elevated HER2-driven tumorigenic, multi-organ metastatic spread, and resistance to anti-HER2 therapy. Collectively, this study defines PRLR as a driver of precise luminal and epithelial differentiation limiting cellular plasticity, stemness, and tumorigenesis and emphasizing the function of pro/forward-differentiation pathways as a foundation for the discovery of anti-cancer therapeutic targets.
PubMed: 33446633
DOI: 10.1038/s41389-020-00297-5 -
Aging Dec 2020Progesterone receptor (PR) isoforms can drive unique phenotypes in luminal breast cancer (BC). Here, we hypothesized that PR-B and PR-A isoforms differentially modify...
Progesterone receptor (PR) isoforms can drive unique phenotypes in luminal breast cancer (BC). Here, we hypothesized that PR-B and PR-A isoforms differentially modify the cross-talk between prolactin and fatty acid synthase (FASN) in BC. We profiled the responsiveness of the FASN gene promoter to prolactin in T47D BC cells constitutively expressing PR-A and PR-B, in the PR-null variant T47D-Y cell line, and in PR-null T47D-Y cells engineered to stably re-express PR-A (T47D-YA) or PR-B (T47D-YB). The capacity of prolactin to up-regulate FASN gene promoter activity in T47D cells was lost in T47D-Y and TD47-YA cells. Constitutively up-regulated FASN gene expression in T47-YB cells and its further stimulation by prolactin were both suppressed by the prolactin receptor antagonist hPRL-G129R. The ability of the FASN inhibitor C75 to decrease prolactin secretion was more conspicuous in T47-YB cells. In T47D-Y cells, which secreted notably less prolactin and downregulated prolactin receptor expression relative to T47D cells, FASN blockade resulted in an augmented secretion of prolactin and up-regulation of prolactin receptor expression. Our data reveal unforeseen PR-B isoform-specific regulatory actions in the cross-talk between prolactin and FASN signaling in BC. These findings might provide new PR-B/FASN-centered predictive and therapeutic modalities in luminal intrinsic BC subtypes.
Topics: 4-Butyrolactone; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Databases, Genetic; Fatty Acid Synthase, Type I; Humans; Interleukin-6; Prolactin; Promoter Regions, Genetic; Protein Isoforms; RNA, Messenger; Receptor Cross-Talk; Receptors, Progesterone; Receptors, Prolactin; Up-Regulation
PubMed: 33335078
DOI: 10.18632/aging.202289 -
Cancer Cell International May 2023Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute...
BACKGROUND
Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still difficult to manage. Thus, new therapeutic approaches are needed. Based on in silico-generated preliminary data and the literature, the role of the prolactin (PRL)-mediated signaling was interrogated in AML.
METHODS
Protein expression and cell viability were determined by flow cytometry. Repopulation capacity was studied in murine xenotransplantation assays. Gene expression was measured by qPCR and luciferase-reporters. SA-β-Gal staining was used as a senescence marker.
RESULTS
The prolactin receptor (PRLR) was upregulated in AML cells, as compared to their healthy counterpart. The genetic and molecular inhibition of this receptor reduced the colony-forming potential. Disruption of the PRLR signaling, either using a mutant PRL or a dominant-negative isoform of PRLR, reduced the leukemia burden in vivo, in xenotransplantation assays. The expression levels of PRLR directly correlated with resistance to cytarabine. Indeed, acquired cytarabine resistance was accompanied with the induction of PRLR surface expression. The signaling associated to PRLR in AML was mainly mediated by Stat5, in contrast to the residual function of Stat3. In concordance, Stat5 mRNA was significantly overexpressed at mRNA levels in relapse AML samples. A senescence-like phenotype, measured by SA-β-gal staining, was induced upon enforced expression of PRLR in AML cells, partially dependent on ATR. Similar to the previously described chemoresistance-induced senescence in AML, no cell cycle arrest was observed. Additionally, the therapeutic potential of PRLR in AML was genetically validated.
CONCLUSIONS
These results support the role of PRLR as a therapeutic target for AML and the further development of drug discovery programs searching for specific PRLR inhibitors.
PubMed: 37208719
DOI: 10.1186/s12935-023-02944-4 -
Reproductive Sciences (Thousand Oaks,... Sep 2022Uterine leiomyomas are benign, estrogen-sensitive, fibrotic smooth muscle cell tumors occurring in the uterine myometrium. Leiomyomas are a considerable health burden,...
Uterine leiomyomas are benign, estrogen-sensitive, fibrotic smooth muscle cell tumors occurring in the uterine myometrium. Leiomyomas are a considerable health burden, with a lifetime prevalence of 80% and limited treatment options. Estrogen and progesterone have positive effects on leiomyoma growth, but little is known about the roles of other hormones. One hormone of interest is prolactin, as it has been described to be present and functional in leiomyomas. The current study investigates prolactin production within leiomyomas and its effects on myometrial cells. RNA isolation and quantitative-PCR of human leiomyoma samples relative to matched adjacent myometrium confirms significant expression of prolactin and dopamine receptor D2, a known regulator of prolactin production and release in the pituitary, with no difference in prolactin receptor expression. Immunohistochemistry confirms increased prolactin in leiomyomas compared to adjacent myometrium and uteri from women without leiomyomas. These results suggest that leiomyomas contain cells that produce prolactin, which may then promote signaling in leiomyoma cells to regulate leiomyoma development/growth. Accordingly, we find that prolactin robustly activates STAT5 and MAPK signaling in rat and human myometrial cell lines. Furthermore, prolactin stimulates expression of myofibroblast markers in rat myometrial cells. Our findings suggest that local prolactin production in leiomyomas may stimulate trans-differentiation of myometrial cells to myofibroblasts, which in turn contributes to the fibrotic nature of leiomyomas.
Topics: Animals; Estrogens; Female; Fibrosis; Humans; Leiomyoma; Myometrium; Prolactin; Rats; Uterine Neoplasms
PubMed: 34724171
DOI: 10.1007/s43032-021-00741-w -
Translational Cancer Research Oct 2020Prolactin (PRL) is a polypeptide hormone secreted by the anterior pituitary to stimulate growth and differentiation of the normal mammary gland. Together with its...
BACKGROUND
Prolactin (PRL) is a polypeptide hormone secreted by the anterior pituitary to stimulate growth and differentiation of the normal mammary gland. Together with its receptor, prolactin receptor (PRLR) have been shown to play a role in breast cancer. This study aimed to examine the roles of and polymorphisms and expression in breast cancer risk and aggressiveness in Thai patients.
METHODS
(rs3756824 C/G and rs2244502 T/A) and (rs37364 G/T and rs249537 A/G) polymorphisms were genotyped by real-time PCR and PRLR expression was assessed by immunohistochemistry (IHC) in breast cancer tissues. The correlations between and polymorphisms and breast cancer susceptibility/aggressiveness as well as the associations between PRLR expression and clinicopathological parameters were determined.
RESULTS
Two hundred and twenty-seven breast cancer patients and 119 matched controls were recruited at the Division of Head Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Thailand from 2010-2014. and polymorphisms were not correlated with breast cancer susceptibility and there was no association between polymorphisms and PRLR expression. PRLR was frequently overexpressed in breast cancer with positive hormone receptors. High expression of PRLR was significantly related to the presence of axillary nodal metastasis and lymphovascular invasion and showed a trend towards poorer outcome.
CONCLUSIONS
There was a correlation between high PRLR expression and aggressive features of breast cancer. PRLR expression might be utilized as a prognostic factor for identification of luminal breast cancer with poorer outcome.
PubMed: 35117242
DOI: 10.21037/tcr-20-1120 -
Animal Biotechnology Nov 2023A total of 266 records of buffalo raised in two experimental herds in Egypt were assessed to detect prolactin () and prolactin receptor () genes' polymorphism using...
A total of 266 records of buffalo raised in two experimental herds in Egypt were assessed to detect prolactin () and prolactin receptor () genes' polymorphism using PCR-Single Strand Conformational Polymorphism (SSCP) and PCR-Restricted Fragment Length Polymorphism (RFLP) techniques as well as to investigate their association with calf birth weight (BW), weaning weight (WW), lactation period (LP), total milk yield (TMY), stillbirth, calving ease (CE), gestation length (GL), postpartum interval to pregnancy (PPIP), calving interval (CI), and age at first calving (AFC). Predicted breeding values were estimated and used in the association with detected genotypes. A monomorphic pattern of the studied 156 bp segment was recorded and absence of its polymorphism in buffalo was corroborated. We also determined polymorphism of reflected in three loci: 2, 4, and 9. Significant differences among 9 genotypes (AA, AB, and BB) were displayed for all studied traits as well as among 2 genotypes, except for CE, while 4 genotypes significantly differed only in BW, WW, TMY, stillbirth, GL, and AFC. In practice, strong associations among genotypes of the gene and the traits of interest candidate this gene to be selective in Egyptian buffalo breeding for improving both productive and reproductive traits.
Topics: Pregnancy; Female; Animals; Prolactin; Receptors, Prolactin; Buffaloes; Egypt; Stillbirth; Genotype
PubMed: 35148254
DOI: 10.1080/10495398.2022.2028160 -
Tijdschrift Voor Psychiatrie 2021Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated... (Review)
Review
BACKGROUND
Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated receptor 1 (TAAR1) agonist and a serotonin 5-HT1a agonist with potential antipsychotic properties.
AIM
To describe the rationale for the development of SEP-363856, the pharmacology of TAAR1/5-HT1a agonists, and the clinical efficacy of SEP-363856.
METHOD
A narrative review of the literature using PubMed, Embase and PsychINFO.
RESULTS
Six publications were identified, one of which was a phase 2 clinical trial with SEP-363856. This phase 2 study shows that SEP-363856 is an effective and well-tolerated antipsychotic; positive, but also negative symptoms decreased; motor side effects (akathisia) and prolactin increase did not occur, while metabolic side effects hardly occurred. Reported side-effects were somnolence and nausea. The antipsychotic activity of SEP-363856 appears to be (pre)clinical not based on D2 antagonism, but on TAAR1 and 5-HT1a agonism.
CONCLUSION
TAAR1 and 5-HT1a agonists such as SEP-363856 may be a treatment option for psychosis. Hopefully they can be further developed into an antipsychotic with a favorable effectiveness and tolerability profile.
Topics: Antipsychotic Agents; Humans; Psychotic Disorders; Receptors, Dopamine; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome
PubMed: 34851520
DOI: No ID Found