A Novel RARβ Isoform Directed by a Distinct Promoter P3 and Mediated by Retinoic Acid in Breast Cancer Cells

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Abstract
Retinoids regulate gene transcription through activating retinoic acid receptors (RARs)/retinoic X receptors (RXRs). Of the three RAR receptors (α, β, and γ), RARβ has been considered a tumor suppressor gene. Here, we identified a novel RARβ isoform-RARβ5 in breast epithelial cells, which could play a negative role in RARβ signaling. Similar to RARβ2, the first exon (59 bp) of RARβ5 is RARβ5 isoform specific, whereas the other exons are common to all of the RARβ isoforms. The first exon of RARβ5 does not contain any translation start codon, and therefore its protein translation begins at an internal methionine codon of RARβ2, lacking the A, B, and part of C domain of RARβ2. RARβ5 protein was preferentially expressed in estrogen receptor-negative breast cancer cells and normal breast epithelial cells that are relatively resistant to retinoids, whereas estrogen receptor-positive cells that did not express detectable RARβ5 protein were sensitive to retinoid treatment, suggesting that this isoform may affect the cellular response to retinoids. RARβ5 isoform is unique among all of the RARs, because a corresponding isoform was not detectable for either RARα or RARγ. RARβ5 mRNA was variably expressed in normal and cancerous breast epithelial cells. Its transcription was under the control of a distinct promoter P3, which can be activated by all-trans-retinoic acid (atRA) and other RAR/RXR selective retinoids in MCF-7 and T47D breast cancer cells. We mapped the RARβ5 promoter and found a region -302/-99 to be the target region of atRA. In conclusion, we identified and initially characterized RARβ5 in normal, premalignant, and malignant breast epithelial cells. RARβ5 may serve as a potential target of retinoids in prevention and therapy studies.