Are prolactin and its receptor involved in the pathogenesis of glioblastoma?

ANTONELA ASAD; CAMILA ZUCCATO; YAEL LASTRA; VINCENT GOFFIN; JIMENA FERRARIS; NAZARENO GONZALEZ; SANTIAGO JORDI ORRILLO; FLORENCE BOUTILLON; DANIEL PISERA; ALEJANDRO NICOLA; ARACELI ABT; EMILIO DE SIMONE; ADRIANA SEILICOVICH; MARIANELA CANDOLFI

Mar del Plata

Congreso; Reunión anual Sociedad Argentina de Investigación Clínica (SAIC) 2019; 2019

Sociedad Argentina de Investigación Clínica

Gliomas are primary brain tumors derived from glial cells. Glioblastomas (GB) are the most frequent and aggressive gliomas. Prolactin (PRL) and its receptor (PRLR) have been detected in GB biopsies. Although PRL has been involved in the development of hormone-dependent tumors, its role in the pathogenesis of GB remains unclear. Our aim was to explore the contribution of PRL and PRLR in GB progression. We have previously found that GB cells express PRL and PRLR, and that the PRL/PRLR pathway increases GB cell proliferation rate and viability. In the current study, we observed that the overexpression of PRL using plasmid transfection significantly increased GB cell viability and decreased cisplatin cytotoxic effect, whereas the overexpression of PRLR antagonist Δ1?9-G129R-hPRL (PRLR-A) showed opposite results. The overexpression of PRLR isoforms inhibited the effect of cisplatin on viability and clonogenicity of GB cells. PRLR blockade using PRLR-A decreased GB cell migration, as assessed by the wound assay. Moreover, zymography of conditioned media from GB cells incubated with PRL showed higher activity of MMP-2 and MMP-9, enzymes involved in GB cell invasion. Transcriptomic meta-analysis of human glioma specimens indicated that PRLR mRNA was present in virtually all grade II-III glioma (GII-III) and GB samples. PRL expression was upregulated in GB biopsies when compared to GII-III. While in the general population tumor PRL/PRLR expression did not correlate with median survival, biological sex-stratified analyses revealed that male patients with PRL+/ PRLRHIGH GB performed worse than PRL+/ PRLRLOW GB. In contrast, all male PRL+/ PRLRHIGH GII-III patients were alive whereas only 30% of PRL+/ PRLRLOW GII-III patients survived after 100 months. These results suggest that PRLR could constitute a therapeutic target for GB treatment and provides additional evidence that sexual dimorphism should be taken into account to improve the care of GB patients.