Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation.
The involvement of human prolactin (hPRL) in breast cancer has been recently reconsidered based on its autocrine/paracrine proliferative effect described in human mammary tumor epithelial cells. Therefore, there is growing interest in the development of potent hPRL antagonists that may inhibit this effect. We previously designed hPRL analogs displaying antagonistic properties in a human transcriptional bioassay. We now report that the most potent of those analogs, G129R-hPRL, antagonizes all hPRL-induced effects analysed in various breast cancer cell lines, including cell proliferation. The analog per se lacks intrinsic agonistic activity on PRL receptor-activated signaling cascades, cell proliferation and apoptosis, indicating that its mode of action only occurs through competitive inhibition of hPRL. We provide some molecular basis of this antagonistic effect by demonstrating that G129R-hPRL competitively inhibits hPRL-activation of the JAK-STAT and MAPK pathways, two signaling cascades involved in the mitogenic effect of hPRL in mammary epithelial cells. This competitive inhibition persists for at least 48 h, as evidenced by long term analysis of STAT5b activation or of progression through cell cycle. These results are the first demonstration at the molecular level that hPRL antagonists interfering with receptor dimerization disrupt signaling events in breast cancer cells, which prevents hPRL-induced cell proliferation.
Llovera
M
M
INSERM Unit 344, Molecular Endocrinology, Faculté de Médecine Necker, Paris, France.
Pichard
C
C
Bernichtein
S
S
Jeay
S
S
Touraine
P
P
Kelly
P A
PA
Goffin
V
V
D019898:Autocrine Communication / Q000187:drug effects*; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019281:Dimerization; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006727:Hormone Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008894:Milk Proteins; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000473:pathology*; D011388:Prolactin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004268:DNA-Binding Proteins; D006727:Hormone Antagonists; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D015534:Trans-Activators; C402398:prolactin, Arg(129)-; D011388:Prolactin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2