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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 RAR
2 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 RAR
2 induction, which strongly suggested that promoter hypermethylation is responsible for RAR
2 underexpression. We compared the outcome of ectopic expression in MCF-7 cells of matched levels of RAR
2 and RARß2. On the basis of a clonogenic assay, RAR
2 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 RAR
2-transfected cells compared with 75 and 77%, respectively, in RARß2-transfected cells. We conclude that the silencing of the RAR
2 promoter by hypermethylation may play a contributory role in the dysregulation of RA signaling in mammary tumorigenesis.
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