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

¹ Department of Surgical Oncology, University of Illinois at Chicago, and ² Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois; and ³ Department of Obstetrics and Gynecology, Kobe University School of Medicine, Kobe, Japan

Retinoids regulate gene transcription through activating retinoic acid receptors (RARs)/retinoic X receptors (RXRs). Of the three RAR receptors (, ß, and ), RARß has been considered a tumor suppressor gene. Here, we identified a novel RARß isoform-RARß5 in breast epithelial cells, which could play a negative role in RARß signaling. Similar to RARß2, the first exon (59 bp) of RARß5 is RARß5 isoform specific, whereas the other exons are common to all of the RARß isoforms. The first exon of RARß5 does not contain any translation start codon, and therefore its protein translation begins at an internal methionine codon of RARß2, lacking the A, B, and part of C domain of RARß2. RARß5 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 RARß5 protein were sensitive to retinoid treatment, suggesting that this isoform may affect the cellular response to retinoids. RARß5 isoform is unique among all of the RARs, because a corresponding isoform was not detectable for either RAR or RAR. RARß5 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 RARß5 promoter and found a region -302/-99 to be the target region of atRA. In conclusion, we identified and initially characterized RARß5 in normal, premalignant, and malignant breast epithelial cells. RARß5 may serve as a potential target of retinoids in prevention and therapy studies.

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