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

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 (RXR) 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 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 induced nucleoplasmic overexpression of RXR and resulted in apoptosis upon treatment with an RXR ligand. This suggests that nucleoplasmic RXR restores retinoid sensitivity. Epitope-tagged RXR and a C-terminus deletion mutant failed to localize to the SFC. Moreover, RXR localization to the SFC was inhibited with RXR C-terminus peptide. This peptide also induced ligand-dependent transactivation on RXRE. Therefore, the RXR C terminus may play a role in the intranuclear localization of RXR. Our results provide evidence that altered localization of RXR to the SFC may be an important factor for the loss of retinoid responsiveness in MDA-MB-231 breast cancer cells.

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