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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 -
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 -
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 -
Seminars in Cell & Developmental Biology Jun 2021Prolactin has a rich mechanistic set of actions and signaling in order to elicit developmental effects in mammals. Historically, prolactin has been appreciated as an... (Review)
Review
Prolactin has a rich mechanistic set of actions and signaling in order to elicit developmental effects in mammals. Historically, prolactin has been appreciated as an endocrine peptide hormone that is responsible for final, functional mammary gland development and lactation. Multiple signaling pathways impacted upon by the microenvironment contribute to cell function and differentiation. Endocrine, autocrine and paracrine signaling are now apparent in not only mammary development, but also in cancer, and involve multiple cell types including those of the immune system. Multiple ligands agonists are capable of binding to the prolactin receptor, potentially expanding receptor function. Prolactin has an important role not only in tumorigenesis of the breast, but also in a number of hormonally responsive cancers such as prostate, ovarian and endometrial cancer, as well as pancreatic and lung cancer. Although pituitary and extra-pituitary sources of prolactin such as the epithelium are important, stromal sourced prolactin is now also being recognized as an important factor in tumor progression, all of which potentially signal to multiple cell types in the tumor microenvironment. While prolactin has important roles in milk production including calcium and bone homeostasis, in the disease state it can also affect bone homeostasis. Prolactin also impacts metastatic cancer of the breast to modulate the bone microenvironment and promote bone damage. Prolactin has a fascinating contribution in both physiologic and pathologic settings of mammals.
Topics: Animals; Disease Models, Animal; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mice; Neoplasm Metastasis; Neoplasms; Prolactin
PubMed: 33109441
DOI: 10.1016/j.semcdb.2020.10.005 -
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 -
Expert Opinion on Therapeutic Targets Nov 2020: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies.... (Review)
Review
: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies. GBM is the most common and aggressive primary brain tumor in adults and the prognosis for patients is dismal; hence researchers are exploring the PRLR pathway as a therapeutic target in this disease. : This paper explores the effects of PRLR activation on the biology of GBM, the correlation between PRL and PRLR expression and GBM progression and survival in male and female patients. Finally, we discuss how a better understanding of the PRLR pathway may allow the development of novel treatments for GBM. : We propose PRL and PRLR as potential prognosis biomarkers and therapeutic targets in GBM. Local administration of PRLR inhibitors using gene therapy may offer a beneficial strategy for targeting GBM cells disseminated in the non-neoplastic brain; however, efficacy and safety require careful and extensive evaluation. The data depicted herein underline the need to (i) improve our understanding of sexual dimorphism in GBM, and (ii) develop accurate preclinical models that take into consideration different hormonal contexts, specific genetic alterations, and tumor grades.
Topics: Adult; Animals; Biomarkers, Tumor; Brain Neoplasms; Female; Genetic Therapy; Glioblastoma; Humans; Male; Molecular Targeted Therapy; Prognosis; Prolactin; Receptors, Prolactin
PubMed: 32896197
DOI: 10.1080/14728222.2020.1821187 -
Animal Biotechnology Dec 2023The objectives of the current study were to identify polymorphism in the prolactin receptor (PRLR) gene among three Egyptian goat breeds (Zaraibi, Damascus, and Barki)...
The objectives of the current study were to identify polymorphism in the prolactin receptor (PRLR) gene among three Egyptian goat breeds (Zaraibi, Damascus, and Barki) and to investigate the association between PRLR genotype, parity, season of kidding, and litter size factors with milk yield and reproductive traits of Zaraibi goats. One hundred and ninety blood samples were collected for DNA extraction, with 110 from Zaraibi, 40 from Barki, and 40 from Damascus breeds. Three genotypes, CC, CT and TT, for the prolactin receptor gene were identified in the 190 DNA samples using restriction fragment length polymorphism and were confirmed by direct sequencing technique. Milk yield during suckling and lactation periods in addition to age at first conception, gestation length, and litter size were determined in 110 Zaraibi goats. The Zaraibi goats recorded the highest heterozygosity (0.495) and the effective number of alleles (1.972). The g.62130C > T SNP showed a significant association ( < 0.01) with suckling, lactation, and total milk yield of Zaraibi goats with the highest values recorded at the third parity. Age at the first conception and gestation length traits were significantly influenced by the kidding season ( < 0.05) with younger age in autumn and shorter length in spring seasons. Milk yield during the suckling period was significantly ( < 0.01) higher in the case of triplets' litter size. The current study showed that litter size and parity played an important role in the amount of Zaraibi goats' milk yield. The g.62130C > T SNP of the PRLR gene may be a useful marker for assisted selection programs to improve goat milk yield during suckling and lactation periods with the heterozygous genotype CT recording the highest values.
Topics: Pregnancy; Female; Animals; Receptors, Prolactin; Alleles; Prolactin; Goats; Egypt; Milk; DNA
PubMed: 37409468
DOI: 10.1080/10495398.2023.2223237 -
Biologie Aujourd'hui 2022Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by lactotroph cells of the anterior pituitary gland. The actions of prolactin are...
Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by lactotroph cells of the anterior pituitary gland. The actions of prolactin are mediated by its transmembrane receptor, PRLR. The principal role attributed to PRL is to stimulate the proliferation and differentiation of the mammary cells required for lactation, but studies of animal models have assigned more than 300 separate actions to this hormone in various species. Hyperprolactinaemia is the prototypical pathological state associated with this hormone. Indeed, hyperprolactinaemia is the most common cause of amenorrhoea due to hypogonadotropic anovulation and is one of the most prevalent endocrine causes of infertility in women. In recent years, the study of conditional or complete Prlr mouse models had improved the understanding concerning the regulation of gonadotroph and lactotroph axes. It is now demonstrated that prolactin exerts autocrine or paracrine actions on lactotroph cells in vivo. One of the major advances was to better understand, using mouse models, the impact of hyperprolactinemia on gonadotroph axis. It is now accepted that hypogonadotropic hypogonadism in patients with hyperprolactinemia is mediated by a decrease of hypothalamic kisspeptin secretion. Gonadotroph axis can be restored by intravenous administration of kisspeptin. However, the mechanisms of lactotroph tumorigenesis in Prlr animals remain incompletely understood and transposable to the human species, since the only patient with biallelic PRLR loss-of-function mutation leading to complete prolactin resistance that has been described so far did not have pituitary adenoma visible on MRI.
Topics: Animals; Female; Humans; Mice; Hyperprolactinemia; Kisspeptins; Models, Animal; Prolactin; Receptors, Prolactin
PubMed: 36744975
DOI: 10.1051/jbio/2022019