Elevated retinoic acid receptor β4 protein in human breast tumor cells with nuclear and cytoplasmic localization

The transcription factor retinoic acid receptor beta(2) (RAR beta(2)) is a potent inhibitor of breast cancer cells in vitro, and studies suggest that RAR beta expression is lost in primary breast cancer. Although RAR beta(2) is selectively down-regulated at the mRNA level in breast tumor cells, we show that expression of an RAR beta protein is elevated in five of five breast tumor cell lines relative to normal human mammary epithelial cells. Subsequent analysis identified this protein as the translation product of the human RAR beta(4) transcript. Unlike the previously characterized mouse RAR beta(4) isoform, the human RAR beta(4) retains only half of a DNA-binding domain and lacks a ligand-independent transactivation domain at its N terminus. The RAR beta(4) protein localizes to the cytoplasm and to subnuclear compartments that resemble nuclear bodies. The structure and preliminary characterizations of human RAR beta(4), coupled with the observation that its expression is greatly elevated in breast tumor cell lines, support the hypothesis that RAR beta(4) functions as a dominant-negative repressor of RAR-mediated growth suppression.