congresos y reuniones científicas
FUNCTIONAL CROSSTALK BETWEEN PROGESTERONE AND GLUCOCORTICOID RECEPTORS IN BREAST CANCER CELLS
OGARA M.F.; RODRIGUEZ SEGUÍ S; SORONELLAS D; NACHT S.; VICENT, G.P.; A. PECCI
San Carlos de Bariloche
Simposio; SISTAM 2015; 2015
The glucocorticoid and progesterone receptors (GR and PR, respectively) are closely related members of the steroid receptor family of transcription factors. Despite they share many similar structural and functional characteristics, including their DNA sequence recognition motif, the cognate hormones display very distinct physiological responses and even in tissues expressing both GR and PR they can exert opposite biological actions in proliferation, differentiation and cell death. In view of the mentioned results, the aim of this project was to identify genome-wide the PR and the GR binding sites (PRBs and GRBs, respectively) in human epithelial breast cancer cell line T47D/1-2, which expresses comparable levels of both receptors and derived from T47D-WT cell line1. Cells were treated for 1 h either with the progestin analog R5020 or the synthetic glucocorticoid dexametasone (DEX) and subjected to the ChIP-seq protocol. We found 28,563 PRBs and 18,538 GRBs upon treatment with the respective ligand. Surprisingly, most of the binding sites of both receptors were located mainly in intergenic regions and introns, and only a small fraction was located in promoter regions. Of the total number of PR binding sites, 14,870 (52 %) were PR exclusive, whereas 4,822 (26 %) of GR binding sites were exclusive or this receptor. Interestingly, we found 13,716 sites shared between both receptors after 60 min of hormone. In order to evaluate whether GR expression in T47D/A1-2 could affect PR function, we analyzed the activity of several progestin target genes with PR and GR binding sites. Of note, genes like SNAI1, CD44, CCND1, EGF and DUSP1 exhibited more transcriptional activity after hormone in T47D-WT compared to T47D/A1-2. Genes repressed by R5020, like ELF5, showed the same behavior with increased transcriptional repression in T47D-WT compared with T47D/A1-2. In addition, progestin-dependent cell proliferation as well as dedifferentiation was also reduced in cells expressing GR. These findings suggest that the presence of GR would interfere on PR dependent function in mammary tumor epithelial cells. 1. Nordeen SK, Kuhnel B, Lawler-Heavner J, Barber DA, Edwards DP. Mol Endocrinol 3: 1270-1278 (1989).