title: Alpha2-adrenoceptor agonists trigger prolactin signaling in breast cancer cells.
abstract: Breast cancer is the most frequent malignancy among women worldwide. We have described the expression of α2-adrenoceptors in breast cancer cell lines, associated with increased cell proliferation and tumor growth. A mitogenic autocrine/paracrine loop of prolactin (Prl) has been described in breast cancer cells. We hypothesized that the α2-adrenergic enhancement of proliferation could be mediated, at least in part, by this Prl loop. In both T47D and MCF-7 cell lines, the incubation with the α2-adrenergic agonist dexmedetomidine significantly increased Prl release into the culture medium (measured by the Nb2 bioassay), this effect being reversed by the α2-adrenergic antagonist rauwolscine. No change in Prl receptors (PrlR) was observed by RT-qPCR in these cell lines. In IBH-6 cells a decrease in Prl secretion was observed at the lower dexmedetomidine concentration. The signaling pathways involved in ovine Prl (oPrl) and dexmedetomidine action were also assessed. Both compounds significantly activated STAT5 and ERK in all three cell lines. In T47D and MCF-7 cell lines also AKT was activated by both Prl and dexmedetomidine. We therefore describe the STAT5 phosphorylation by an α2-adrenergic agonist, dexmedetomidine. In T47D cells, the α2-adrenergic stimulation of cell proliferation is probably mediated, at least in part, by the Prl autocrine/paracrine loop, because this effect is abrogated by the specific PrlR antagonist Δ1-9-G129R-hPrl. The implication of Prl loop describes a novel mechanism of action of this GPCR.
authors.affiliation: Instituto Ángel H. Roffo, Av. San Martín 5481, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Lilian Fedra
authors.initials: LF
authors.lastname: Castillo
authors.affiliation: Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Ezequiel M
authors.initials: EM
authors.lastname: Rivero
authors.affiliation: Inserm U1151/Institut Necker Enfants Malades (INEM), 14 Rue Maria Helena Vieira Da Silva, CS61431 75993 Paris, Cedex 14, France; Université Paris Descartes, Sorbonne-Paris-Cité, France. Electronic address: vincent.goffin@inserm.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.affiliation: Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: isabel.luthy@ibyme.conicet.gov.ar.
authors.forename: Isabel Alicia
authors.initials: IA
authors.lastname: Lüthy
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D045744:Cell Line, Tumor; D020927:Dexmedetomidine / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D020927:Dexmedetomidine; D011388:Prolactin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Cell signaling; IBH-6; MCF-7; T47D