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Up-regulation of the kinase gene SGK1 by progesterone activates the AP-1–NDRG1 axis in both PR-positive and -negative breast cancer cells

Preoperative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independently of their progesterone receptor (PR) status. This observation raises the question how progesterone affects the outcome of PR-negative cancer. Here, using microarray and RNA-Seq–b...

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Detalles Bibliográficos
Autores principales: Godbole, Mukul, Togar, Trupti, Patel, Kuldeep, Dharavath, Bhasker, Yadav, Neelima, Janjuha, Sharan, Gardi, Nilesh, Tiwary, Kanishka, Terwadkar, Prachi, Desai, Sanket, Prasad, Ratnam, Dhamne, Hemant, Karve, Kunal, Salunkhe, Sameer, Kawle, Dhananjay, Chandrani, Pratik, Dutt, Shilpee, Gupta, Sudeep, Badwe, Rajendra A., Dutt, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298595/
https://www.ncbi.nlm.nih.gov/pubmed/30337371
http://dx.doi.org/10.1074/jbc.RA118.002894
Descripción
Sumario:Preoperative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independently of their progesterone receptor (PR) status. This observation raises the question how progesterone affects the outcome of PR-negative cancer. Here, using microarray and RNA-Seq–based gene expression profiling and ChIP-Seq analyses of breast cancer cells, we observed that the serum- and glucocorticoid-regulated kinase gene (SGK1) and the tumor metastasis–suppressor gene N-Myc downstream regulated gene 1 (NDRG1) are up-regulated and that the microRNAs miR-29a and miR-101-1 targeting the 3′-UTR of SGK1 are down-regulated in response to progesterone. We further demonstrate a dual-phase transcriptional and post-transcriptional regulation of SGK1 in response to progesterone, leading to an up-regulation of NDRG1 that is mediated by a set of genes regulated by the transcription factor AP-1. We found that NDRG1, in turn, 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. This model helps decipher the molecular basis of observations in a randomized clinical trial of the effect of progesterone on breast cancer and has therefore the potential to improve the prognosis of breast cancer patients receiving preoperative progesterone treatment.