Elevated retinoic acid receptor β(4) protein in human breast tumor cells with nuclear and cytoplasmic localization

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