title: The chemopreventive effect of mifepristone on mammary tumorigenesis is associated with an anti-invasive and anti-inflammatory gene signature.
abstract: Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR- and non-PR-mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-α-positive (ER(+)) transgenic mice expressing the dominant-negative Pax8PPARγ (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a three-fold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with an expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the downregulation of genes associated with metabolism, inflammation, and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yuan
authors.forename: Geeta
authors.initials: G
authors.lastname: Upadhyay
authors.forename: Jin
authors.initials: J
authors.lastname: Lu
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Robert I
authors.initials: RI
authors.lastname: Glazer
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D002273:Carcinogens; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D018890:Chemoprevention / Q000379:methods; D004353:Drug Evaluation, Preclinical; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000235:genetics*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D015735:Mifepristone / Q000494:pharmacology / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness / Q000235:genetics; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D006727:Hormone Antagonists; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D015735:Mifepristone; D015127:9,10-Dimethyl-1,2-benzanthracene