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Research Articles: Therapeutics, Targets, and Development

Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells

¹ Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas and ² Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois

Requests for reprints: Varsha Gandhi, Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Box 71, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-2989; Fax: 713-794-4316. E-mail: vgandhi{at}mdanderson.org

Abstract

Although glucocorticoids play an important role in the treatment of multiple myeloma, some patients do not respond or develop resistance. The glucocorticoid receptor (GR), a single gene, mediates the effects of glucocorticoids. Using a model system of a multiple myeloma cell line sensitive to glucocorticoids and its early and late resistant variants, we have analyzed mutations in the GR gene, detected the presence of different transcriptional isoforms, quantified their levels of expression, and identified the promoters that regulate their expression. Levels of GR transcripts were comparable with the expression of total GR protein. Development of resistance correlates with an overall reduction in GR mRNA levels. This decrease in GR levels is neither due to mutation of the gene nor due to methylation. GR is the predominant isoform in the sensitive cell line decreasing in expression in the early resistant cells and virtually undetectable in late resistant cells. GR-P is expressed at equivalent levels in both sensitive and early resistant cells, whereas in the late resistant cells, GR-P is the predominant isoform. GR-A is only expressed in the early resistant cell line. GRß is the least expressed isoform in all cell lines. Interestingly, the level of expression of exon 1-exon 2 RNA fragments remains similar in sensitive and resistant cell lines. Resistant cells became sensitive to glucocorticoids after GR transfection. In conclusion, we show different patterns of expression of the GR isoforms and provide evidence that a decline in the expression of GR may be associated with development of resistance. [Mol Cancer Ther 2006;5(12):3062–70]

Grant support: National Cancer Institute grant CA85915.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ http://www-genome.wi.mit.edu/genome_software/other/primer3.html.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 6/12/06; revised 9/24/06; accepted 10/26/06.