Please use this identifier to cite or link to this item:
|Web of Science®
|ANTI-proliferative transcriptional effects of medroxyprogesterone acetate in Estrogen receptor positive breast cancer cells are predominantly mediated by ThE progesterone receptor.
|The Journal of Steroid Biochemistry and Molecular Biology, 2019; 199:105548-105548
|Nicole L.Moore, Adrienne R.Hanson, Esmaeil Ebrahimie, Theresa E.Hickey, Wayne D.Tilley
|Medroxyprogesterone acetate (MPA) is a first generation progestin that has been in clinical use for various hormonal conditions in women since the 1960s. Although developed as a progesterone receptor (PR) agonist, MPA also has strong binding affinity for other steroid receptors. This promiscuity confounds the mechanistic action of MPA in target cells that express multiple steroid receptors. This study is the first to assess the relative contribution of progesterone, androgen and glucocorticoid receptors in mediating the transcriptional activity of MPA on endogenous targets in breast cancer cells that endogenously express all three receptors at comparable levels. Gene expression profiling in estrogen receptor positive (ER+) ZR-75-1 breast cancer cells demonstrated that although the MPA-regulated transcriptome strongly overlapped with that of Progesterone (PROG), 5α-dihydrotestosterone (DHT) and Dexamethasone (DEX), it clustered most strongly with that of PROG, suggesting that MPA predominantly acts via the progesterone receptor (PR) rather than androgen receptor (AR) or glucocorticoid receptor (GR). Subsequent experiments manipulating levels of these receptors, either through specific culture conditions or with lentiviral shRNAs targeting individual receptors, also revealed a stronger contribution of PR compared to AR and GR on the expression of endogenous target genes that are either commonly regulated by all ligands or specifically regulated only by MPA. A predominant contribution of PR to MPA action in ER + T-47D breast cancer cells was also observed, although a stronger role for AR was evident in T-47D compared to that observed in ZR-75-1 cells. Network analysis of ligand-specific and commonly regulated genes demonstrated that MPA utilises different transcription factors and signalling pathways to inhibit proliferation compared with PROG. This study reaffirms the importance of PR in mediating MPA action in an endogenous breast cancer context where multiple steroid receptors are co-expressed and has potential implications for PR-targeting therapeutic strategies in ER + breast cancer.
|© 2019 Elsevier Ltd. All rights reserved.
|Appears in Collections:
|Aurora harvest 4
Research Branch publications
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.