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We and others previously reported that up-regulation of retinoic acid receptor-alpha (RAR alpha) RNA and protein levels is elicited by estrogen in human breast cancer cells. We set out to determine the mechanism by which estrogen up-regulates RAR alpha. Cloning of 500 bp of the human (h) RAR alpha 1 promoter has been reported previously; we obtained this 500-bp DNA sequence by PCR techniques from human genomic DNA and tested its activity in the context of a luciferase-containing reporter vector in Hep G2 cell contransactivation assays. Estradiol elicited a 6- to 8-fold increase in luciferase activity from the reporter vector driven by hRAR alpha promoter sequence between -491 and +36 bp that was dependent on the presence of contransfected estrogen receptor (ER). Analysis of various truncated versions of this promoter sequence indicated that two regions of the sequence are sensitive to estrogen stimulation. The first resides in the region -49 to -79 bp upstream from the transcription start site and conferred approximately 2-fold activation by estrogen. This region does not contain a consensus estrogen response element, and ER binding to this DNA sequence was not observed. The second responsive sequence lies at -455 to -491 bp and conferred in additional 4- to 6-fold activation by estrogen. This upstream sequence contains two A/TGGTCA half-sites; however, direct binding of ER to this sequence was not observed. Additionally, ER DNA-binding domain mutants that are not capable of binding to DNA were just as effective as wild type ER in their ability to confer estrogen responsiveness to the RAR alpha promoter, implying that ER DNA-binding ability is not required for the estrogen-induced increase in transcriptional activity. Mutation of either half-site or of an additional immediate downstream sequence in the context of the -491 to +36 bp construct reduced the luciferase activity induction by estrogen from 6-fold to 1.5- to 2-fold. Placement of the region between -455 to -491 bp upstream of an SV40 promoter-driven luciferase vector conferred approximately 20- to 30-fold stimulation of luciferase activity by estrogen in an ER-dependent manner. The ER antagonists, 4-hydroxy-tamoxifen, keoxifene, and ICI 164384, each acted as weak agonist via the hRAR alpha promoter in contransactivation assays, exhibiting 20-30% of the efficacy that was demonstrated by estradiol. Interestingly, upon treatment of MCF7 cells with estradiol or the ER antagonists, increased levels of RAR alpha RNA and protein were observed with the antagonists as well as with estrogen.

Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor-alpha 1 promoter via a novel sequence.