<i>Hypothesis</i> Prolactin is tumorigenic to human breast: dispelling the myth that prolactin‐induced mammary tumors are rodent‐specific

Harvey, Philip W.

doi:10.1002/jat.1772

Cited by 23 publications

(11 citation statements)

References 81 publications

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“…There is accumulating epidemiological, clinical, and biological evidence confirming a role of PRL in human breast cancer risk [8, 443, 444]. However, although an association has been demonstrated, a cause and effect relationship is yet to be established [445].…”

Section: Consequences Of Hprlmentioning

confidence: 99%

The Effects of Novel and Newly Approved Antipsychotics on Serum Prolactin Levels: A Comprehensive Review

et al. 2014

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Since the 1970s, clinicians have increasingly become more familiar with hyperprolactinemia (HPRL) as a common adverse effect of antipsychotic medication, which remains the cornerstone of pharmacological treatment for patients with schizophrenia. Although treatment with second-generation antipsychotics (SGAs) as a group is, compared with use of the first-generation antipsychotics, associated with lower prolactin (PRL) plasma levels, the detailed effects on plasma PRL levels for each of these compounds in reports often remain incomplete or inaccurate. Moreover, at this moment, no review has been published about the effect of the newly approved antipsychotics asenapine, iloperidone and lurasidone on PRL levels. The objective of this review is to describe PRL physiology; PRL measurement; diagnosis, causes, consequences and mechanisms of HPRL; incidence figures of (new-onset) HPRL with SGAs and newly approved antipsychotics in adolescent and adult patients; and revisit lingering questions regarding this hormone. A literature search, using the MEDLINE database (1966–December 2013), was conducted to identify relevant publications to report on the state of the art of HPRL and to summarize the available evidence with respect to the propensity of the SGAs and the newly approved antipsychotics to elevate PRL levels. Our review shows that although HPRL usually is defined as a sustained level of PRL above the laboratory upper limit of normal, limit values show some degree of variability in clinical reports, making the interpretation and comparison of data across studies difficult. Moreover, many reports do not provide much or any data detailing the measurement of PRL. Although the highest rates of HPRL are consistently reported in association with amisulpride, risperidone and paliperidone, while aripiprazole and quetiapine have the most favorable profile with respect to this outcome, all SGAs can induce PRL elevations, especially at the beginning of treatment, and have the potential to cause new-onset HPRL. Considering the PRL-elevating propensity of the newly approved antipsychotics, evidence seems to indicate these agents have a PRL profile comparable to that of clozapine (asenapine and iloperidone), ziprasidone and olanzapine (lurasidone). PRL elevations with antipsychotic medication generally are dose dependant. However, antipsychotics having a high potential for PRL elevation (amisulpride, risperidone and paliperidone) can have a profound impact on PRL levels even at relatively low doses, while PRL levels with antipsychotics having a minimal effect on PRL, in most cases, can remain unchanged (quetiapine) or reduce (aripiprazole) over all dosages. Although tolerance and decreases in PRL values after long-term administration of PRL-elevating antipsychotics can occur, the elevations, in most cases, remain above the upper limit of normal. PRL profiles of antipsychotics in children and adolescents seem to be the same as in adults. The hyperprolactinemic effects of antipsychotic medication are mostly correlated with their affi...

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Section: Consequences Of Hprlmentioning

confidence: 99%

The Effects of Novel and Newly Approved Antipsychotics on Serum Prolactin Levels: A Comprehensive Review

et al. 2014

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“…PRL is a potent mitogen that stimulates growth of rodent mammary tumors. In humans, PRL increases cell proliferation in mammary carcinoma cell lines, primary cultures, and breast tumor explants and it has a role in the development and progression of breast cancer [ 1 - 4 ]. The human prolactin receptor (hPRLR) has several forms, including the long form and short forms which are products of alternative splicing with variable lengths in their cytoplasm domains [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Prolactin induces up-regulation of its cognate receptor in breast cancer cells via transcriptional activation of its generic promoter by cross-talk between ERα and STAT5

2014

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Prolactin (PRL) serves a critical role in breast cancer progression via activation of its cognate receptor. These studies reveal up-regulation of PRLR gene expression by PRL in absence of estradiol in MCF-7 and T47D breast cancer cells. PRL/PRLR via activation of STAT5 that binds a GAS-element in the PRLR gene and the participation of ERα stimulates PRLR transcription/expression. PRL/PRLR induces phosphorylation of ERα through the JAK2/PI3K/MAPK/ERK and JAK2/HER2 activated pathways. The increased recruitment of phospho-ERα, induced by PRL to Sp1 and C/EBPβ at PRLR promoter sites, is essential for PRL-induced PRLR transcription. This recruitment is prevented by blockade of PRL expression using RNA interference or ERα phosphorylation with specific inhibitors of PI3K and ERK. Direct evidence is provided for local actions of PRL, independent of estradiol, in the up-regulation of PRLR transcription/expression by an activation-loop between STAT5 and the phospho-ERα/Sp1/C/EBPβ complex with requisite participation of signaling mechanisms. PRL's central role in the up-regulation of PRLR maximizes the action of the endogenous hormone. This study offers mechanistically rational basis for invasiveness fueled by prolactin in refractory states to adjuvant therapies in breast cancer.

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“…PRL has been definitively associated with the onset and progression of human breast cancer by increasing cell proliferation (reviewed in [6-8]), and may contribute to metastasis by inducing the motility of human breast cancer cells [9]. The human PRL receptor (PRLR) is widely expressed in diverse tissues, and signaling through PRLR initiates activation of several intracellular pathways, the most well-characterized being the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway (reviewed in [3,10]).…”

Section: Introductionmentioning

confidence: 99%

The transcriptional responsiveness of LKB1 to STAT-mediated signaling is differentially modulated by prolactin in human breast cancer cells

Linher‐Melville

Singh

2014

BMC Cancer

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BackgroundLiver kinase 1 (LKB1) is an important multi-tasking protein linked with metabolic signaling, also controlling polarity and cytoskeletal rearrangements in diverse cell types including cancer cells. Prolactin (PRL) and Signal transducer and activator of transcription (STAT) proteins have been associated with breast cancer progression. The current investigation examines the effect of PRL and STAT-mediated signaling on the transcriptional regulation of LKB1 expression in human breast cancer cells.MethodsMDA-MB-231, MCF-7, and T47D human breast cancer cells, and CHO-K1 cells transiently expressing the PRL receptor (long form), were treated with 100 ng/ml of PRL for 24 hours. A LKB1 promoter-luciferase construct and its truncations were used to assess transcriptional changes in response to specific siRNAs or inhibitors targeting Janus activated kinase 2 (JAK2), STAT3, and STAT5A. Real-time PCR and Western blotting were applied to quantify changes in mRNA and protein levels. Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays were used to examine STAT3 and STAT5A binding to the LKB1 promoter.ResultsConsistent with increases in mRNA, the LKB1 promoter was up-regulated by PRL in MDA-MB-231 cells, a response that was lost upon distal promoter truncation. A putative GAS element that could provide a STAT binding site mapped to this region, and its mutation decreased PRL-responsiveness. PRL-mediated increases in promoter activity required signaling through STAT3 and STAT5A, also involving JAK2. Both STATs imparted basally repressive effects in MDA-MB-231 cells. PRL increased in vivo binding of STAT3, and more definitively, STAT5A, to the LKB1 promoter region containing the GAS site. In T47D cells, PRL down-regulated LKB1 transcriptional activity, an effect that was reversed upon culture in phenol red-free media. Interleukin 6, a cytokine activating STAT signaling in diverse cell types, also increased LKB1 mRNA levels and promoter activity in MDA-MB-231 cells.ConclusionsLKB1 is differentially regulated by PRL at the level of transcription in representative human breast cancer cells. Its promoter is targeted by STAT proteins, and the cellular estrogen receptor status may affect PRL-responsiveness. The hormonal and possibly cytokine-mediated control of LKB1 expression is particularly relevant in aggressive breast cancer cells, potentially promoting survival under energetically unfavorable conditions.

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Hypothesis Prolactin is tumorigenic to human breast: dispelling the myth that prolactin‐induced mammary tumors are rodent‐specific

Cited by 23 publications

References 81 publications

The Effects of Novel and Newly Approved Antipsychotics on Serum Prolactin Levels: A Comprehensive Review

The Effects of Novel and Newly Approved Antipsychotics on Serum Prolactin Levels: A Comprehensive Review

Prolactin induces up-regulation of its cognate receptor in breast cancer cells via transcriptional activation of its generic promoter by cross-talk between ERα and STAT5

The transcriptional responsiveness of LKB1 to STAT-mediated signaling is differentially modulated by prolactin in human breast cancer cells

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