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Molecular and Cellular Biology, May 2004, p. 3972-3982, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3972-3982.2004

Altered Localization of Retinoid X Receptor {alpha} Coincides with Loss of Retinoid Responsiveness in Human Breast Cancer MDA-MB-231 Cells

T. Tanaka, B. L. Dancheck, L. C. Trifiletti, R. E. Birnkrant, B. J. Taylor, S. H. Garfield, U. Thorgeirsson, and L. M. De Luca*

National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255

Received 4 September 2003/ Returned for modification 26 September 2003/ Accepted 16 January 2004

To understand the mechanism of retinoid resistance, we studied the subcellular localization and function of retinoid receptors in human breast cancer cell lines. Retinoid X receptor {alpha} (RXR{alpha}) localized throughout the nucleoplasm in retinoid-sensitive normal human mammary epithelial cells and in retinoid-responsive breast cancer cell line (MCF-7), whereas it was found in the splicing factor compartment (SFC) of the retinoid-resistant MDA-MB-231 breast cancer cell line and in human breast carcinoma tissue. In MDA-MB-231 cells, RXR{alpha} was not associated with active transcription site in the presence of ligand. Similarly, ligand-dependent RXR homo- or heterodimer-mediated transactivation on RXR response element or RARE showed minimal response to ligand in MDA-MB-231 cells. Infecting MDA-MB-231 cells with adenoviral RXR{alpha} induced nucleoplasmic overexpression of RXR{alpha} and resulted in apoptosis upon treatment with an RXR ligand. This suggests that nucleoplasmic RXR{alpha} restores retinoid sensitivity. Epitope-tagged RXR{alpha} and a C-terminus deletion mutant failed to localize to the SFC. Moreover, RXR{alpha} localization to the SFC was inhibited with RXR{alpha} C-terminus peptide. This peptide also induced ligand-dependent transactivation on RXRE. Therefore, the RXR{alpha} C terminus may play a role in the intranuclear localization of RXR{alpha}. Our results provide evidence that altered localization of RXR{alpha} to the SFC may be an important factor for the loss of retinoid responsiveness in MDA-MB-231 breast cancer cells.

* Corresponding author. Mailing address: National Institutes of Health, Bldg. 37, Rm. 4054C, 37 Convent Dr., Bethesda, MD 20892-4255. Phone: (301) 496-2698. Fax: (301) 496-8709. E-mail: delucal{at}mail.nih.gov.

Molecular and Cellular Biology, May 2004, p. 3972-3982, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.3972-3982.2004




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