PRLR

Official Full Name

prolactin receptor

Organism

Homo sapiens

GeneID

5618

Background

This gene encodes a receptor for the anterior pituitary hormone, prolactin, and belongs to the type I cytokine receptor family. Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor. Several alternatively spliced transcript variants encoding different membrane-bound and soluble isoforms have been described for this gene, which may function to modulate the endocrine and autocrine effects of prolactin in normal tissue and cancer. [provided by RefSeq, Feb 2011]

Synonyms

HPRL; MFAB; hPRLrI; RI-PRLR;

Bio Chemical Class

Cytokine receptor

Protein Sequence

MKENVASATVFTLLLFLNTCLLNGQLPPGKPEIFKCRSPNKETFTCWWRPGTDGGLPTNYSLTYHREGETLMHECPDYITGGPNSCHFGKQYTSMWRTYIMMVNATNQMGSSFSDELYVDVTYIVQPDPPLELAVEVKQPEDRKPYLWIKWSPPTLIDLKTGWFTLLYEIRLKPEKAAEWEIHFAGQQTEFKILSLHPGQKYLVQVRCKPDHGYWSAWSPATFIQIPSDFTMNDTTVWISVAVLSAVICLIIVWAVALKGYSMVTCIFPPVPGPKIKGFDAHLLEKGKSEELLSALGCQDFPPTSDYEDLLVEYLEVDDSEDQHLMSVHSKEHPSQGMKPTYLDPDTDSGRGSCDSPSLLSEKCEEPQANPSTFYDPEVIEKPENPETTHTWDPQCISMEGKIPYFHAGGSKCSTWPLPQPSQHNPRSSYHNITDVCELAVGPAGAPATLLNEAGKDALKSSQTIKSREEGKATQQREVESFHSETDQDTPWLLPQEKTPFGSAKPLDYVEIHKVNKDGALSLLPKQRENSGKPKKPGTPENNKEYAKVSGVMDNNILVLVPDPHAKNVACFEESAKEAPPSLEQNQAEKALANFTATSSKCRLQLGGLDYLDPACFTHSFH

Open

Disease

Fallopian tube cancer, Ovarian cancer, Peritoneal cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

The PRLR (Prolactin Receptor) gene is located on human chromosome 5p13.2 and encodes a transmembrane protein belonging to the type I cytokine receptor superfamily. It contains at least 10 exons and generates multiple isoforms via alternative splicing, including membrane-bound and soluble receptor forms. These isoforms differ in tissue distribution and functional properties: the long isoform (long PRLR) fully activates downstream signaling, whereas short isoforms (e.g., human ΔS1-PRLR) often act as dominant negative regulators, modulating signaling intensity through competitive ligand binding or inhibition of receptor dimerization. Promoter diversity allows PRLR expression to be regulated by multiple transcription factors, including C/EBPβ and Sp1, supporting tissue-specific physiological responses. PRLR is widely expressed, not only in mammary tissue but also in liver, kidney, adrenal glands, gonads (ovary and testis), brain (particularly the hypothalamus and pituitary), and immune cells. In the brain, PRLR interacts with cerebrospinal prolactin (PRL) to form a short negative feedback loop that induces hypothalamic dopamine synthesis, essential for maintaining PRL homeostasis.

Signaling Pathways

The binding of prolactin (PRL) to PRLR induces receptor dimerization, activating multiple intracellular pathways. The JAK2-STAT5 pathway is the canonical downstream signaling cascade: receptor dimerization recruits and activates Janus kinase 2 (JAK2), which phosphorylates STAT5 transcription factors, enabling their nuclear translocation to regulate target gene expression. PRLR also activates the MAPK/ERK pathway (cell proliferation and differentiation), PI3K-Akt pathway (cell survival and metabolism), and Src kinase pathway (cell migration). Signaling effects are tissue-specific: in mammary tissue, PRLR promotes lactation-related gene expression; in the corpus luteum, it regulates progesterone secretion; in the male reproductive system, it supports sperm survival by inhibiting Src kinase activation and stimulating AKT signaling. This signaling diversity is partly due to tissue-specific isoform expression and cross-talk with other cytokine receptors, such as the growth hormone receptor (GHR).

Figure 1. PRLR signaling and pathway cross-talk in cancer showing activation by PRL, GH, or PL with context-specific effects in breast and prostate cancer. (Damiano JS, et al., 2013)

Biological Functions

PRLR-mediated effects extend beyond lactation, encompassing reproductive regulation, osmoregulation, immune modulation, and behavioral responses. In reproduction, the PRL-PRLR axis modulates mammalian reproductive cycles: moderate activation maintains luteal function and progesterone synthesis, while excessive activation inhibits GnRH pulsatility, causing gonadal suppression. In the Wu Xi white goose model, PRLR mRNA peaks during nest-occupying behavior, 4–45 times higher than in laying or non-laying periods, with synchronous upregulation in the hypothalamus, pituitary, and ovary, highlighting its central role in avian reproductive behavior. In male health, abnormal PRLR signaling is associated with sexual dysfunction: hyperprolactinemia (HPRL) patients show 88–92% incidence of erectile dysfunction and 84.2% reduced libido, resulting from secondary hypogonadism and direct inhibition of penile smooth muscle and central dopaminergic pathways.

Immune and Metabolic Roles

PRLR is expressed in T cells, B cells, and macrophages, regulating cytokine secretion and inflammatory responses. Clinical studies reveal significantly reduced PRLR expression in anal gland tissue of patients with perianal abscesses, correlating with poor postoperative healing. In metabolism, PRLR signaling participates in osmoregulation: in tilapia, high PRLR expression in gills and intestines modulates ion transport to maintain water-salt balance. Early embryonic upregulation of PRLR supports its key role in development. Species-specific differences exist: human PRLR ligand-binding domains share high homology with GHR, allowing cross-reactivity with growth hormone, while rodent PRLR can bind placental lactogen. Soluble PRLR isoforms are more abundant in human serum, buffering excess PRL, whereas in mice, membrane receptor shedding predominates.

Clinical Associations and Disease Mechanisms

Hyperprolactinemia (HPRL), defined as serum PRL >20 ng/mL, is a hallmark of PRLR pathway dysregulation, caused by pituitary adenomas, hypothalamic dysfunction, or drug-induced inhibition of dopamine D2 receptors. Male HPRL often manifests as a "silent killer," with sexual dysfunction and reduced bone density due to impaired osteoblast differentiation and disrupted vitamin D metabolism. In cancer, PRLR signaling exhibits tissue-specific effects: in breast cancer, PRLR-STAT5 activation promotes a differentiated phenotype associated with favorable prognosis, whereas in prostate cancer, PRL-PRLR-STAT3/5 activation drives proliferation and angiogenesis, contributing to therapy resistance. PRLR dysfunction also underlies reproductive disorders: defective sperm PRLR expression leads to premature capacitation, reduced motility, and acrosome reaction defects. In females, PRLR polymorphisms increase recurrent miscarriage risk by impairing immune tolerance during decidualization. PRLR may also influence non-reproductive diseases, including impaired wound healing and metabolic disorders such as non-alcoholic fatty liver disease, through regulation of insulin sensitivity and lipid metabolism.

Therapeutic Strategies and Challenges

Therapeutic interventions targeting PRLR include dopamine agonists (e.g., cabergoline) and selective PRLR antagonists. Cabergoline normalizes PRL levels in most microadenoma and 70–80% of macroadenoma patients, restoring gonadal function; however, 10–20% exhibit resistance, associated with altered isoform ratios or D2 receptor polymorphisms. Next-generation PRLR antagonists (e.g., LFA102, hPRL-G129R) block PRL binding or receptor dimerization, showing anti-tumor activity in prostate cancer clinical trials, though single-agent efficacy is limited. Dual-function molecules (e.g., PRLR/GHR antagonists) and soluble PRLR neutralizing antibodies show promise in preclinical models for tumor suppression and bone density improvement. Gene therapy approaches, such as AAV-mediated dominant-negative PRLR vectors, reduce tumor volume in pituitary adenoma models. Precision medicine requires patient stratification based on PRLR isoform expression or polymorphisms, alongside targeted delivery strategies to minimize systemic side effects.

Reference

Damiano JS, Wasserman E. Molecular pathways: blockade of the PRLR signaling pathway as a novel antihormonal approach for the treatment of breast and prostate cancer. Clin Cancer Res. 2013 Apr 1;19(7):1644-50.
Kavarthapu R, Anbazhagan R, Dufau ML. Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer. Cancers (Basel). 2021 Sep 18;13(18):4685.
Standing D, Dandawate P, Anant S. Prolactin receptor signaling: A novel target for cancer treatment - Exploring anti-PRLR signaling strategies. Front Endocrinol (Lausanne). 2023 Jan 13;13:1112987.

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