Association of prolactin receptor (<i>PRLR</i>) variants with prolactinomas

Gorvin, Caroline M; Newey, Paul; Rogers, Alice; Stokes, Victoria; Neville, Matt J.; Lines, Kate E; Ntali, Georgia; Lees, Peter; Morrison, Patrick J.; Singhellakis, P.N.; Malandrinou, Fotini Ch.; Karavitaki, Niki; Grossman, Ashley; Karpe, Fredrik

doi:10.1093/hmg/ddy396

Cited by 28 publications

(48 citation statements)

References 56 publications

(88 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bromocriptine resistance has been commonly reported to accompany decreased levels of D2R 4 - 6 , 23 , 28 , 29 . Moreover, antagonizing estrogen and dopamine can regulate the endocrine functions of the other, and estrogen may decrease D2R expression or attenuate functional coupling with its downstream effector 17 , 30 , 31 . Based on these findings, D2R was also investigated in the present study.…”

Section: Resultsmentioning

confidence: 99%

“…To further investigate the synergistic effects of fulvestrant and bromocriptine on downstream signaling molecules, ERα- and bromocriptine-induced signaling was observed in MMQ cells treated with bromocriptine and fulvestrant alone or in combination. Key downstream markers of ERα- or bromocriptine-induced signaling, such as p38, AKT, ERK, JNK and cyclin D1 9 , 17 , 30 , 42 - 44 , were investigated by western blotting following co-culture with bromocriptine (25 μM) and fulvestrant (20 nM) for 72 h. Enhanced pJNK1/2, pERK1/2 and p38, but decreased cyclin D1 expression was observed in the combination group, while pAKT was not obviously altered (Fig. 7 D).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, Delgrange et al 41 also reported that prolactinomas possess lower ERα expression levels in men, and that ERα expression is associated with a higher tumor grade, resistance to treatment and a poorer prognosis. Besides ERα, previous studies have indicated that most prolactinomas express PRLR 17 , and that PRL increases estrogen responsiveness in multiple tissue types 41 . Moreover, an increased circulating PRL level is linked to the risk of ER-positive breast cancer 40 .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas

Zhang¹,

Yang²,

Zhang³

et al. 2020

Int. J. Med. Sci.

View full text Add to dashboard Cite

Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas

Zhang¹,

Yang²,

Zhang³

et al. 2020

Int. J. Med. Sci.

View full text Add to dashboard Cite

show abstract

“…Anti-proliferative responses to the inhibition of the mammalian target of rapamycin (mTOR) pathway have been reported in in vitro studies with aggressive pituitary tumors [106]. Particularly for prolactinomas, Gorvin et al showed that certain variants of the prolactin receptor, like the Asn492Ile one, are associated with increased signaling by this pathway and cellular proliferation, and that everolimus was antagonizing these effects [107]. A case report described a patient with a DA-resistant prolactinoma that underwent multiple surgical resections and radiotherapy 6 years before a trial of everolimus (10 mg/ day) was attempted [108].…”

Section: Inhibitors Of Mammalian Target Of Rapamycin (Mtor)mentioning

confidence: 99%

Dopamine agonist resistant prolactinomas: any alternative medical treatment?

Souteiro

Karavitaki

2019

Pituitary

View full text Add to dashboard Cite

Consensus guidelines recommend dopamine agonists (DAs) as the mainstay treatment for prolactinomas. In most patients, DAs achieve tumor shrinkage and normoprolactinemia at well tolerated doses. However, primary or, less often, secondary resistance to DAs may be also encountered representing challenging clinical scenarios. This is particularly true for aggressive prolactinomas in which surgery and radiotherapy may not achieve tumor control. In these cases, alternative medical treatments have been considered but data on their efficacy should be interpreted within the constraints of publication bias and of lack of relevant clinical trials. The limited reports on somatostatin analogues have shown conflicting results, but cases with optimal outcomes have been documented. Data on estrogen modulators and metformin are scarce and their usefulness remains to be evaluated. In many aggressive lactotroph tumors, temozolomide has demonstrated optimal outcomes, whereas for other cytotoxic agents, tyrosine kinase inhibitors and for inhibitors of mammalian target of rapamycin (mTOR), higher quality evidence is needed. Finally, promising preliminary results from in vitro and animal reports need to be further assessed and, if appropriate, translated in human studies.

show abstract

“…kinase-2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) pathway (8). Thus, the JAK2/STAT5 pathway may contribute to drug resistance in prolactinomas.…”

Section: Pimozide Augments Bromocriptine Lethality In Prolactinoma Cementioning

confidence: 99%

Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways

et al. 2020

View full text Add to dashboard Cite

As hyperprolactinemia is observed in patients with bromocriptine-resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) signaling pathway, the STAT5 inhibitor, pimozide, may inhibit cell proliferation and reverse bromocriptine resistance in prolactinoma cells. In the present study, compared with bromocriptine or pimozide alone, the combination of pimozide and bromocriptine exerted enhanced reduction in cell growth and proliferation, and increased apoptosis and cell cycle arrest in bromocriptine-resistant prolactinoma cells. A reduction in phospho-STAT5, cyclin d1 and B-cell lymphoma extra-large (Bcl-xL) expression levels were observed in cells treated with the combination of drugs. In addition, pimozide suppressed spheroid formation of human pituitary adenoma stem-like cells, and reduced the protein expression of the cancer stem cell markers, cd133 and nestin. Pimozide did not exert any additional antitumor activity in STAT5-knockdown primary culture cells of human bromocriptine-resistant prolactinomas. Furthermore, Pimozide combined with bromocriptine treatment significantly reduced human prolactinoma xenograft growth. Western blot and immunohistochemical analyses also demonstrated significant inhibition of cell proliferation and stem cell marker proteins in vivo. collectively, these data indicated that pimozide treatment reduced prolactinoma growth by targeting both proliferating cells and stem cells, at least in part, by inhibiting the STAT5/Bcl-xL and STAT5/cyclin d1 signaling pathways.

show abstract

Association of prolactin receptor (PRLR) variants with prolactinomas

Cited by 28 publications

References 56 publications

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas

Dopamine agonist resistant prolactinomas: any alternative medical treatment?

Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways

Contact Info

Product

Resources

About