FUNCTIONAL ANALYSIS OF GLUCOCORTICOID AND PROGESTERONE RECEPTOR CROSSTALK

GUTIERREZ, M.; ALVES, C.; PECCI, A.; OGARA, MF.

MAR DEL PLATA - BUENOS AIRES - ARGENTINA

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAL 2023; 2023

SAIC SAB AAFE AACYTAL

The glucocorticoid and progesterone receptors (GR and PR, respectively) are closely related members of the steroid receptorfamily of transcription factors. Despite they share similar structural and functional properties, as their DNA sequence recognition motif, the cognate hormones display very distinct physiological responses and even in tissues expressing both receptors they exert opposite biological actions in proliferation, differentiation and cell death. Results from our group demonstrated an antagonistic effect of activated GR on PR-dependent features in mammary epithelial cells. To evaluate whether GR activation could affect PR function, we analyzed the expression of several progestin target genes in MCF-7L cells which express both PR and GR. RT-qPCRs of selected genes show that GR activation by Dexamethasone (DEX) [10 nM] inhibited the R5020 [10 nM]-dependent induction of STAT5A, SNAI1A and EGFR, wherein potentiated R5020-mediated GREB1 and ELF5 expression induction. These results were confirmed by siRNA-medi-ated GR knockdown, where the progestin-dependent expression of those genes was restored. Moreover, cell cycle analyses performed in cells treated for 18 h with R5020 show that the percentage of cells accumulated in S phase was significantly higher compared to untreated cells (13.7±0.7% vs 10.2±0.3%). DEX alone did not affect S phase accumulation (10.3±0.6%) but inhibited R5020-mediated action (10.9±0.9%). To assess whether the presence of GR affects proliferation, survival and cell migration induced by progestin, clonogenic and wound healing assays were performed in MCF-7L cells. Clonogenic assay shows that treatment with R5020+DEX decreases the proportion of colonies by half compared to R5020 alone. In the same way, wound closure decreased by 20% when treated with both ligands compared to R5020 alon e. These results seem to indicate that activated GR modulates PR-dependent cell proliferationand migration in mammary tumor epithelial cells.