Differential regulation of SGK1 by progesterone activates AP-1/NDRG1 genomic axis in PR-positive and negative breast cancer cells

Pre-operative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independent of their progesterone receptor (PR) status, raising a question about how progesterone affects the outcome of PR-negative cells. Here, we identify up-regulation of a Serum- and glucocorticoid-regulated kinase gene, SGK1 and an N-Myc Downstream Regulated Gene 1, NDRG1, along with down-regulation of miR-29a and miR-101-1 targeting 3’UTR region of SGK1, to differential extents in a PR dependent manner in breast cancer cells. We further demonstrate a novel dual-phase transcriptional and post-transcriptional regulation of SGK1 in response to progesterone leading to up-regulation of a tumor metastasis suppressor gene, NDRG1, mediated by a set of AP-1 network genes. The NDRG1 further inactivates a set of kinases impeding the invasion and migration of breast cancer cells. In summary, we propose a model for the mode of action of progesterone in breast cancer deciphering the molecular basis of a randomized clinical trial studying the effect of progesterone in breast cancer with a potential to improve the prognosis of breast cancer patients for receiving pre-operative progesterone treatment.