Protein phosphatase 2A regulates estrogen receptor alpha (ER) expression through modulation of ER mRNA stability

Protein phosphatase 2A (PP2A) is a ubiquitously expressed member of the serine-threonine phosphatase family that is involved in regulation of many cellular processes including transcription, translation, cellular metabolism, and apoptosis. Because of a correlation between PP2A and estrogen receptor alpha (ER) expression in several human breast cancer cell lines, the effect of PP2A on regulation of ER expression in the human breast cancer cell line MCF-7 was studied. Inhibition of PP2A using the pharmacologic inhibitor okadaic acid at 250 nm for 16 h resulted in a 60% reduction in PP2A activity in MCF-7 cells concurrent with a 75% reduction in ER mRNA and protein expression. Similar results were obtained with a small interfering RNA probe that specifically inhibited PP2A expression. ER promoter studies showed that regulation of ER through the PP2A pathway did not occur through transcriptional activation. Rather, PP2A mediated ER expression through modulation of ER mRNA stability through degradation of ER mRNA, reversible with concomitant treatment with the proteasomal inhibitor MG 132. These data suggest a novel pathway controlling ER expression resulting from the activation of PP2A, potentially providing a novel therapeutic target.