A Comprehensive Analysis Of The Transcriptional Effects Of Progesterone Receptor Isoforms A And B Identifies Vegf, Pdgf And Stat3 As Therapeutic Targets.

Progesterone prevents development of endometrial cancers through its receptors A (PRA) and B (PRB) although the molecular mechanisms have yet to be fully characterized. In this study, we performed a global analysis of gene regulation by progesterone using human endometrial cancer cells that express heterologous progesterone receptors. Functional replicate Affymetrix microarrays encompassing 54,000 transcripts were performed for two independent experiments. Data suggest that progesterone exerts the growth-limiting effects in endometrium via down-regulation of several growth factors important in angiogenesis and cell proliferation. In particular, progesterone down-regulates the vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and signal transducer and activator of transcription 3 (STAT3) genes. Down-regulation of these pro-growth pathways required the co-expression of both PR isoforms A and B, whereas expression of either isoform alone resulted in unchanged or even elevated levels of PDGF and STAT3 transcripts. Our study identifies these pathways as central to the growth limiting effects of progesterone in endometrial cancer and suggests that these factors constitute important targets for future therapeutic interventions. We also provide a comprehensive catalogue of the transcriptional effects of PR isoforms in endometrial cancer for future reference. Citation Format: Kimberly K. Leslie, Stephanie M. Leiva, Donghai Dai, Yuping Zhang, Kristina W. Thiel. A comprehensive analysis of the transcriptional effects of progesterone receptor isoforms A and B identifies VEGF, PDGF and STAT3 as therapeutic targets [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO005.