Regulation of Estrogen Receptor Alpha through novel function of HMGA1a.-Towards a novel breast cancer therapy-

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HMGA1a, known as a DNA-binding transcription factor, was found to induce alternative splicing through novel sequence-specific RNA-binding. We found an HMGA1a RNA-binding site in Estrogen Receptor alpha(ERα) pre-mRNA. HMGA1a binds an RNA sequence 33 nucleotides upstream the 5' splice site of ERα exon 1.Interestingly, HMGA1a induces ERα46 isoform mRNA expression by exon skipping of ERα exon 1, and an RNA decoy of the HMGA1a RNA binding site inhibits ERα46 isoform mRNA expression in cultured MCF-7 mammary carcinoma cells. The HMGA1a RNA binding site in ERα exon 1 is located adjacently upstream a pseudo 5' splice site. Thus, HMGA1a traps U1 snRNP to this upstream 5' splice site and leads to dysfunction of the authentic 5' splice site of ERα exon 1.In this way, exon skipping is induced and consequent expression of ERα46 isoform is achieved through alternative splicing. Confirming the decrease of ERα46 protein expression in MCF-7 cells expressing the RNA decoy of HMGA1a RNA binding site, a stable transfectant of MCF-7 cells was established. This stable transfectant was implanted subcutaneously to ovarectomized nude mice with estrogen pellet, resulting in attenuated growth of the implanted cells. Since ERα46 isoform protein is known to inhibit the estrogen response of full length ERα, the findings shown here "an RNA decoy of HMGA1a improves estrogen response of MCF-7 cells by regulating alternative splicing of ERα" will give us a clue in deciphering the mechanism of estrogen resistance in ERα positive mammary carcinoma.