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Frontiers in Endocrinology 2022Prolactin (PRL) is a peptide hormone mainly secreted from the anterior pituitary gland. PRL is reported to play a role in pregnancy, mammary gland development, immune... (Review)
Review
Prolactin (PRL) is a peptide hormone mainly secreted from the anterior pituitary gland. PRL is reported to play a role in pregnancy, mammary gland development, immune modulation, reproduction, and differentiation of islet cells. PRL binds to its receptor PRLR, which belongs to a superfamily of the class I cytokine receptor that has no intrinsic kinase activity. In canonical signaling, PRL binding to PRLR induces downstream signaling including JAK-STAT, AKT and MAPK pathways. This leads to increased cell proliferation, stemness, migration, apoptosis inhibition, and resistance to chemotherapy. PRL-signaling is upregulated in numerous hormone-dependent cancers including breast, prostate, ovarian, and endometrial cancer. However, more recently, the pathway has been reported to play a tumor-promoting role in other cancer types such as colon, pancreas, and hepatocellular cancers. Hence, the signaling pathway is an attractive target for drug development with blockade of the receptor being a potential therapeutic approach. Different strategies have been developed to target this receptor including modification of PRL peptides (Del1-9-G129R-hPRL, G129R-Prl), growth hormone receptor/prolactin receptor bispecific antibody antagonist, neutralizing antibody LFA102, an antibody-drug conjugate (ABBV-176) of the humanized antibody h16f (PR-1594804) and pyrrolobenzodiazepine dimer, a bispecific antibody targeting both PRLR and CD3, an half-life extended fusion protein containing PRLR antagonist PrlRA and albumin binding domain. There have also been attempts to discover and develop small molecular inhibitors targeting PRLR. Recently, using structure-based virtual screening, we identified a few antipsychotic drugs including penfluridol as a molecule that inhibits PRL-signaling to inhibit PDAC tumor progression. In this review, we will summarize the recent advances in the biology of this receptor in cancer and give an account of PRLR antagonist development for the treatment of cancer.
Topics: Male; Humans; Prolactin; Receptors, Prolactin; Signal Transduction; Hyperprolactinemia; Carrier Proteins; Neoplasms
PubMed: 36714582
DOI: 10.3389/fendo.2022.1112987 -
Frontiers in Endocrinology 2022The prolactin receptor (PRLR) is a member of the lactogen/cytokine receptor family, which mediates multiple actions of prolactin (PRL). PRL is a major hormone in the... (Review)
Review
The prolactin receptor (PRLR) is a member of the lactogen/cytokine receptor family, which mediates multiple actions of prolactin (PRL). PRL is a major hormone in the proliferation/differentiation of breast epithelium that is essential for lactation. It is also involved in breast cancer development, tumor growth and chemoresistance. Human PRLR expression is controlled at the transcriptional level by multiple promoters. Each promoter directs transcription/expression of a specific non-coding exon 1, a common non-coding exon 2 and coding exons E3-11. The identification of exon 11 of PRLR led to finding of alternative spliced products and two novel short forms (SF) that can inhibit the long form (LF) of PRLR activity with relevance in physiological regulation and breast cancer. Homo and heterodimers of LF and SF are formed in the absence of PRL that acts as a conformational modifier. Heterodimerization of SF with LF is a major mechanism through which SF inhibits some signaling pathways originating at the LF. Biochemical/molecular modeling approaches demonstrated that the human PRLR conformation stabilized by extracellular intramolecular S-S bonds and several amino acids in the extracellular D1 domain of PRLR SF are required for its inhibitory actions on PRLR LF-mediated functions. Studies in breast cancer cells demonstrated that the transcription of PRLR was directed by the preferentially utilized PIII promoter, which lacks an estrogen responsive element. Complex formation of non-DNA bound ERα dimer with Sp1 and C/EBPβ dimers bound to their sites at the PRLR promoter is required for basal activity. Estradiol induces transcriptional activation/expression of the PRLR gene, and subsequent studies revealed the essential role of autocrine PRL released by breast cancer cells and CDK7 in estradiol-induced PRLR promoter activation and upregulation. Other studies revealed stimulation of the PRLR promoter activity and PRLR LF protein by PRL in the absence of estrogen the STAT5/phospho-ERα activation loop. Additionally, EGF/ERBB1 can induce the transcription of PRLR independent of estrogen and prolactin. The various regulatory modalities contributing to the upregulation of PRLR provide options for the development of therapeutic approaches to mitigate its participation in breast cancer progression and resistance.
Topics: Amino Acids; Breast Neoplasms; Epidermal Growth Factor; Estradiol; Estrogen Receptor alpha; Estrogens; Female; Humans; Prolactin; Receptors, Cytokine; Receptors, Prolactin; STAT5 Transcription Factor
PubMed: 36187116
DOI: 10.3389/fendo.2022.949396 -
Hormone and Metabolic Research =... Apr 2019Prolactin is a peptide hormone known to have multiple functions. However, the role of prolactin has been extensively studied only in female physiology and its function... (Review)
Review
Prolactin is a peptide hormone known to have multiple functions. However, the role of prolactin has been extensively studied only in female physiology and its function in male reproduction still remains majorly unexplored. Studies in rodents and humans have demonstrated the presence of prolactin and its receptor in testes, thereby suggesting a possible role during spermatogenesis. Experimental evidences from prolactin and prolactin receptor deficient male rodent models as well as studies done in hypo- and hyper-prolactinemic males hint at neuroendocrine and reproductive abnormalities. Nonetheless, there still remains a lot of ambiguity on the exact role of prolactin and its receptor in male reproduction. This review summarizes in depth on the role of prolactin in spermatogenesis.
Topics: Animals; Humans; Male; Models, Animal; Prolactin; Receptors, Prolactin; Reproduction; Signal Transduction; Testis
PubMed: 30840999
DOI: 10.1055/a-0859-1144 -
Journal of Molecular Endocrinology Nov 2016Prolactin and prolactin receptor signaling and function are complex in nature and intricate in function. Basic, pre-clinical and translational research has opened up our... (Review)
Review
Prolactin and prolactin receptor signaling and function are complex in nature and intricate in function. Basic, pre-clinical and translational research has opened up our eyes to the understanding that prolactin and prolactin receptor signaling function differently within different cellular contexts and microenvironmental conditions. Its multiple roles in normal physiology are subverted in cancer initiation and progression, and gradually we are teasing out the intricacies of function and therapeutic value. Recently, we observed that prolactin has a role in accelerating the time to bone metastasis in breast cancer patients and identified the mechanism by which prolactin stimulated breast cancer cell-mediated lytic osteoclast formation. The possibility that the prolactin receptor is a marker for metastasis, and specifically bone metastasis, is one that may have to be put into the context of the different variants of prolactin, different prolactin receptor isoforms and intricate signaling pathways that are regulated by the microenvironment. The more complete the picture, the better one can test biomarker identity and design clinical trials to test therapeutic intervention. This review will cover the recent advances and highlight the complexity of prolactin receptor biology.
Topics: Alternative Splicing; Animals; Biomarkers, Tumor; Bone Neoplasms; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2; Ligands; Molecular Targeted Therapy; Neoplasm Metastasis; Pituitary Gland; Prognosis; Prolactin; Protein Isoforms; Receptors, Prolactin; Risk; STAT5 Transcription Factor; Signal Transduction; Tumor Microenvironment
PubMed: 27658959
DOI: 10.1530/JME-16-0150 -
Endocrine Oct 1998Most prolactin (PRL) in the circulation is produced by the pituitary. However, a wide variety of traditional target tissues of the hormone have also been shown to... (Review)
Review
Most prolactin (PRL) in the circulation is produced by the pituitary. However, a wide variety of traditional target tissues of the hormone have also been shown to produce their own prolactin. The amount produced per cell is low, but may well be sufficient for autocrine/paracrine activity. Although dopamine agonists allow one to study the target tissue effects of pituitary PRL, other agents, such as PRL receptor (PRLR) antagonists, are needed to analyze autocrine/paracrine loops. With PRLR antagonists, it should be possible to dissect out the role of extrapituitary prolactin in both the normal physiology, and the pathophysiology of various tissues. In tissues where the locally produced PRL may promote disease, such antagonists have the potential to be important therapeutics. This article briefly, but critically, reviews current understanding of PRL-receptor interactions and initial signaling, and describes the development of both growth hormone (GH) and PRL antagonists within that context. In the final section, results with a very potent PRL antagonist further one theme of the article, which is whether the simple receptor dimerization model explains all signal transduction following PRLR binding.
Topics: Animals; Cytokines; Dimerization; Hormone Antagonists; Human Growth Hormone; Humans; Prolactin; Receptors, Prolactin; Signal Transduction
PubMed: 9867245
DOI: 10.1385/endo:9:2:121 -
Nature Reviews. Endocrinology Jun 2019The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the... (Review)
Review
The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.
Topics: Animals; Female; Genetic Pleiotropy; Health Status; Homeostasis; Humans; Hyperprolactinemia; Osteoporosis; Prolactin; Receptors, Prolactin
PubMed: 30899100
DOI: 10.1038/s41574-019-0194-6 -
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 -
Endocrinology Nov 2022Most breast cancer deaths are caused by malignant estrogen receptor-positive breast tumors that later recur as metastatic disease. Prolactin (PRL) has been documented as...
Most breast cancer deaths are caused by malignant estrogen receptor-positive breast tumors that later recur as metastatic disease. Prolactin (PRL) has been documented as a factor promoting breast cancer development and metastasis. We therefore developed superactive prolactin receptor (PRLR) antagonists aimed at blocking PRL action. We purified 12 novel mutants to homogeneity as monomers, and the most potent antagonist was over 95-fold more active than the previously reported weak antagonist, the mutant Del 1-9 human PRL G129R. This enhanced antagonistic activity resulted mostly from prolonged interaction with the extracellular domain (ECD) of PRLR. All mutants were properly refolded, as indicated by interaction with human PRLR-ECD and by circular dichroism analysis. We then prepared monopegylated variants of the most active mutants to extend their biological half-life in vivo.
Topics: Humans; Female; Receptors, Prolactin; Breast Neoplasms
PubMed: 36351045
DOI: 10.1210/endocr/bqac186 -
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 -
Lupus 2001Within the immune system, multiple isoforms of the human prolactin receptor (PRLr) serve to mediate the effects of its ligand (PRL). Now numbering four, these isoforms... (Review)
Review
Within the immune system, multiple isoforms of the human prolactin receptor (PRLr) serve to mediate the effects of its ligand (PRL). Now numbering four, these isoforms are structurally and functionally distinct, demonstrating significant differences in ligand affinities, kinetics of transduction and the transduction proteins activated. The proximal transduction pathways activated during PRLr-associated signaling include the tyrosine kinases Jak2, Fyn and Tec, the phosphatase SHP-2, the guanine nucleotide exchange factor Vav, and the signaling suppressor SOCS. Differential activation of these pathways may contribute to the pleiotropism of PRL action in tissues of the immune system.
Topics: Animals; Gene Expression Profiling; Guanine Nucleotide Exchange Factors; Humans; Protein Isoforms; Protein-Tyrosine Kinases; Receptors, Prolactin; Signal Transduction
PubMed: 11721697
DOI: 10.1191/096120301717164949