Disease relevance of PRL

• Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant prolactinomas [1].
• There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia [1].
• PRL- and ACTH-secreting pituitary adenomas cannot be visualized, but clinically nonfunctioning pituitary adenomas are visualized in 75% of cases with 111In-DTPA-octreotide [2].
• When dopamine (0.01-0.1 microM) or bromocriptine (0.01-0.1 microM) was added to the culture media, a significant inhibition of GH and PRL secretion from adenoma cells from acromegalic patients was observed [3].
• In contrast, the PRL responses of patients with weight loss exceeding 10 lb were significantly greater than those of either controls or the other depressed patients [4].

Psychiatry related information on PRL

• The PRL response was greater in patients with affective disorders [5].
• Both the information obtained from a review of the literature on the influence of stress on PRL secretion and our own results strongly suggest that contrary to common opinion, there is no evidence at all that psychological stress affects PRL secretion in man [6].
• The TSH and PRL responses were compared with those obtained in a group of control patients without a history of alcohol abuse [7].
• Sleep-related PRL release was less than normal in women with narcolepsy, with or without sleep apnea [8].
• In contrast, MPOA infusions of the control hormone, wild-type human PRL, in Exp 3 did not delay the onset of maternal behavior [9].

High impact information on PRL

• It includes discussions on various aspects of the stress response, the hypothalamic-pituitary-adrenal and -gonadal axes, corticotropin releasing hormone, luteinizing hormone releasing hormone, interleukin-1 and -6, corticosteroids, estrogens, testosterone, dehydroepiandrosterone, growth hormone, prolactin, and thyroid hormone [10].
• Drug therapy may play an increasing role, especially dopamine agonists, which control either hGH or prolactin secretion and can cause shrinkage of tumor tissue [11].
• Luteinizing hormone (LH) from the anterior pituitary is important for normal development and function of the corpus luteum in most mammals, although growth hormone, prolactin, and estradiol also play a role in several species [12].
• Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals [13].
• Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well [13].

Chemical compound and disease context of PRL

• Octreotide therapy is of no value in most patients with Prolactin (PRL)- and adrenocorticotrophic (ACTH)-secreting pituitary tumors [2].
• Osmotic mini-pump coinfusion of estrogen and antiestrogen abrogated estrogen-induced pituitary pttg expression in vivo, suppressed serum PRL concentrations by 88%, and attenuated prolactin-secreting pituitary tumor growth by 41% in rats [14].
• Synergistic action of prolactin (PRL) and androgen on PRL-inducible protein gene expression in human breast cancer cells: a unique model for functional cooperation between signal transducer and activator of transcription-5 and androgen receptor [15].
• To determine the impact of induced hypo- and hypercalcemia on TRH (400 micrograms)-stimulated TSH and PRL release, healthy subjects (n = 11) were infused with 5% glucose in water (n = 11), disodium EDTA (n = 11), or calcium gluconate (n = 7) [16].
• To examine this hypothesis the expression of the sex steroid and PRL receptors was examined in 20 human breast cancer cell lines and 123 primary breast cancers [17].

Biological context of PRL

• Several potential components of the signal transduction pathways have been identified, but as yet none has clearly been shown to be able to mimic the effect of PRL or GH [18].
• No single second messenger mediating the action of either PRL or GH has been identified [18].
• An assay has been developed to measure the functional activity of different forms of PRL receptor by cotransfecting a milk protein fusion gene specific to PRL coupled to a reporter-gene along with the cDNA of the PRL receptor [18].
• Human growth hormone (hGH) elicits a diverse set of biological activities including lactation that derives from binding to the prolactin (PRL) receptor [19].
• The mean ocntent of PRL in the pituitary gland increased sharply from 14.8 plus or minus 4.6 ng at 15-19 wk to 405 plus or minus 142 ng at 20-24 wk and 542 plus or minus ng at 25-29 wk gestation [20].

Anatomical context of PRL

• Since PRL has been implicated in T cell function and human GH can interact with the PRL receptor, DW/J dwarf mice were treated with either ovine GH (ovGH) (20 micrograms/d) or ovine PRL (ovPRL) (20 micrograms/d) [21].
• The PRL-binding protein has a very high affinity for the hormone, almost 10 times higher than the affinity of the mammary gland membrane receptor [22].
• Furthermore, PRL receptors were demonstrated on four cell lines of human and mouse origin [23].
• At concentrations of CsA from 10(-10) through 10(-8) M, the amount of PRL bound to MNC markedly increased to ca. 400% of controls, whereas CsA concentrations of 10(-6) and 10(-5) M totally inhibited PRL binding to lymphocytes [23].
• Finally, PRL receptors were identified on purified populations of T and B lymphocytes isolated from human spleens, and CsA again inhibited PRL binding at concentrations of 10(-7) and 10(-6) M [23].

Associations of PRL with chemical compounds

• Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation [1].
• Several lines of evidence support the view that high plasma estrogen levels characteristic of gestation act directly on the fetal anterior hypophysis to stimulate PRL secretion or to sensitize the secretory mechanism of the lactotrope, increasing its responsiveness to other stimuli [20].
• Norepinephrine, likewise, caused a suppression of PRL secretion from adenomatous and nonadenomatous pituitary cells [3].
• The values for PRL, GH, and TSH at baseline and after protirelin stimulation were normal [24].
• The increases in plasma levels of prolactin (PRL) and growth hormone (GH) following intravenous administration of the 5-hydroxytryptamine precursor tryptophan (100 mg/kg) were assessed in 30 depressed patients and 30 control subjects [4].
• Insulin suppressed PRL expression and release from differentiated adipocytes but moderately stimulated PRL release from nondifferentiated cells [25].
• Premenopausal mean nighttime PRL (P = 0.026) and cortisol (P = 0.018) were higher during EPT compared with placebo [26].

Physical interactions of PRL

• This hPRL variant binds one-sixth as strongly as wild-type hGH, but shares only 26 percent overall sequence identity with hGH [27].
• However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05) [28].
• Disruption of Stat binding to the distal GAS site destroys PRL-induced promoter activity, whereas disruption of the proximal site has no effect [29].
• Decidualized human endometrial stromal cells transfected with 3 kb of the extrapituitary PRL (exon 1a) promoter coupled to a luciferase expression vector responded to IL-2 (10 ng/mL) with a significant decrease in luciferase activity [30].
• EGF stimulation is mediated by increased synthesis of c-fos and c-jun, resulting in AP-1 binding to the proximal hPRL pituitary promoter [31].

Enzymatic interactions of PRL

• Dissociation of Janus kinase 2 and signal transducer and activator of transcription 5 activation after treatment of Nb2 cells with a molecular mimic of phosphorylated prolactin [32].
• Further, Stat1 alpha but not Stat1 beta is preferentially tyrosine phosphorylated in response to PRL stimulation [33].

Co-localisations of PRL

• By combined in situ hybridization and immunohistochemical examination, Pit-1 mRNA and ER mRNA were often colocalized with prolactin immunoreactivities [34].
• Immunoreactive tissue kallikrein was co-localized with prolactin in all the eleven prolactin-secreting adenomas of the human anterior pituitary gland examined in this study [35].

Regulatory relationships of PRL

• However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas [36].
• Prolactin activates Stat1 but does not antagonize Stat1 activation and growth inhibition by type I interferons in human breast cancer cells [37].
• A similar additive relationship was observed on IFN alpha/beta- and PRL-induced Stat3 tyrosine phosphorylation [37].
• Therefore, GH probably exerts its effects as a human macrophage-activating factor through either GH or PRL receptors, without requiring production of IGF-I [38].
• These data provide strong evidence for the involvement of a tyrosine kinase in PRL signal transduction and suggest the presence of a tyrosine kinase within the activated PRL receptor complex [39].
• Predictably, the ability of PRL to activate Stat5 and AP-1 was inversely related in mammary cell lines [40].

Other interactions of PRL

• PRL and GH are hormones with a wide spectrum of actions [18].
• Therefore, hPRL is the preferred ligand for the assessment of prolactin receptor levels in human breast cancer biopsy specimens [41].
• Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas [36].
• In contrast, suppression of prolactin is mediated mainly by SSTR2 [28].
• Despite significant mutual use of Stats by IFNs and PRL, these results indicated a high degree of signaling specificity in the two receptor systems, and that cytoplasmic levels of Stat proteins were not limiting [37].

Analytical, diagnostic and therapeutic context of PRL

• We have now tested this mutant in a sensitive MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-ESTA (eluted stain assay) bioassay using rat PRL receptors in the Nb2 cell line [42].
• Here, we show by reverse transcriptase-polymerase chain reaction and immunohistology that, contrary to a previous report, human skin and normal human scalp hair follicles (HFs), in particular, express both PRL and PRL receptors (PRL-R) at the mRNA and protein level [43].
• Furthermore, in vitro incubation of affinity-purified PRL receptor complexes from PRL-stimulated cells with ATP in the presence of a tyrosine phosphatase inhibitor, resulted in a 10-15-fold increase in the phosphotyrosine content of p120, as revealed by antiphosphotyrosine immunoblotting [39].
• Cyclosporine (CsA), an immunosuppressive cyclic endecapeptide utilized to prolong graft survival in human organ transplant patients, affects PRL binding to MNC [23].
• We have shown by EMSA that PRL induces Stat5a and 5b to bind to the distal GAS site, and immunoprecipitation and subsequent Western analysis of nuclear extracts from PRL-treated cells indicate that Stat5a and 5b can interact as a heterodimer in this system [29].

References