CELL TYPE SPECIFIC PR AND ERA GENE REGULATION IN ENDOMETRIAL CANCER CELLS

ALEJANDRO LA GRECA; NICOLAS BELLORA; PATRICIA SAGUETA

Buenos Aires

Congreso; Joint Meeting of Bioscience Societies 2017; 2017

Argentine Society of Clinical Investigation (SAIC)

Estrogen (E2) and Progesterone (Pg) and their specific receptorsER and PR respectively are major determinants in the developmentand progression of breast and endometrial malignancies. We havestudied the cell specificity of E2 and synthetic progestin R5020 actionin human Ishikawa endometrial cancer cell line and comparedit to similar genomic strategies in human T47D breast cancer cellline. Both hormones regulate pathways linked to cell proliferation inthe breast and endometrial cancer cells, through different gene networksand signaling pathways. Using ChIPseq, we identified ~1,400binding sites for PR (PRbs) and ~1,900 for ERalfa (ERbs) which arelargely specific for Ishikawa and distal (>50kb) to TSS (FDR cutofffor peak calling q = 0.05; FDR cutoff for downstream analysisq<10-5). Long-range interactions in chromatin structured genomeanalyzed by HiC showed that Ishikawa and T47D cells exhibit distinctopen and closed chromatin compartments, which correlate withdifferent hormone receptor binding distribution and gene regulationas indicated in Pgr and Alpp genes. Among Ishikawa specific sites,the most representative motives found in PRbs were PRE, SOX andPAX, whereas in ERbs they were ERE and PAX. PR and ER bindmostly to non-common sites that exhibit their corresponding consensussequences, and are adjacent to Pax2 binding. Increased levelsof PR by E2 treatment resulted in enhanced R5020-dependent PRbinding to chromatin with a stronger association to ER and Pax2binding, while overexpression of PR by introducing one copy of pgrgene produced different PRbs. In conclusion, the endometrial specifichormone response results in part from specific chromatin compartments,unique receptor binding sites and selective TFs bindingpartners.