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Retinoic Acid Receptor 2 Is a Growth Suppressor Epigenetically Silenced In MCF-7 Human Breast Cancer Cells¹

Departments of Medicine [E. F. F., A. A., S. W., R. M. L.] and Pathology (I. J. B.), Mount Sinai School of Medicine, New York, New York 10029-6574, and Leukaemia Research Fund Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom [A. Z.]

Retinoic acid (RA) receptor (RAR) ß2 has been shown to be underexpressed in human breast cancer cells, including MCF-7 cells, and recent reports have suggested that hypermethylation of the RARß2 promoter and 5'-UTR is the underlying cause. Here we show that RAR2 is also underexpressed in MCF-7 breast cancer cells, at both the message and the protein level, relative to normal or nontumorigenic breast epithelial cells. Bisulfite sequencing of the CpG island in the RAR2 promoter revealed highly penetrant and uniform cytosine methylation in MCF-7 cells. Pretreatment with the DNA methyltransferase inhibitor, azacytidine, followed by treatment with RA and a histone deacetylase inhibitor, trichostatin A, resulted in partial promoter demethylation and RAR2 induction, which strongly suggested that promoter hypermethylation is responsible for RAR2 underexpression. We compared the outcome of ectopic expression in MCF-7 cells of matched levels of RAR2 and RARß2. On the basis of a clonogenic assay, RAR2 displayed ligand-dependent growth-suppressive activity similar to that of RARß2; thus, 10 and 20 nM RA inhibited clonogenic growth by 52 and 80%, respectively, in RAR2-transfected cells compared with 75 and 77%, respectively, in RARß2-transfected cells. We conclude that the silencing of the RAR2 promoter by hypermethylation may play a contributory role in the dysregulation of RA signaling in mammary tumorigenesis.

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