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Protein Kinase A Exhibits Selective Modulation of Estradiol-Dependent Transcription in Breast Cancer Cells that Is Associated with Decreased Ligand Binding, Altered Estrogen Receptor Promoter Interaction, and Changes in Receptor Phosphorylation

Department of Biochemistry and Cancer Biology, Health Science Campus, University of Toledo, Toledo, Ohio 43614

Address all correspondence and requests for reprints to: Brian G. Rowan, Ph.D., Department of Structural & Cellular Biology, SL49, Tulane University School of Medicine and the Louisiana Cancer Research Consortium, 1430 Tulane Avenue, New Orleans, Louisiana 70112. E-mail: browan{at}tulane.edu.

Inhibition of protein kinase A (PKA) promotes estrogen-dependent growth of MCF7 breast cancer cells, although the mechanisms by which PKA regulates estrogen receptor (ER) function remain unclear. In this study elevation of cAMP by forskolin/3-isobutyl-1-methylxanthine (F/I) suppressed estradiol-dependent MCF7 and T47D breast cancer cell growth but not tamoxifen-resistant MCF7-LCC2 cells. Although F/I induced ligand independent activation of ER, F/I also decreased estradiol-dependent reporter gene transcription. Overexpression of PKA or PKA inhibitor (PKI) demonstrated that F/I effects on repression of estradiol action occurred through the PKA pathway. 8CPT-2Me-cAMP, a selective inducer of non-PKA signaling, did not alter ER-dependent transcription. In contrast to F/I effects on reporter genes, F/I exhibited gene-specific effects on endogenous, ER-regulated genes. F/I enhanced estradiol induction of pS2 and cMyc but repressed estradiol induction of cyclin D1 mRNA and protein in MCF7 cells. To explore likely mechanisms by which F/I regulated ER, experiments examined estradiol binding, Hsp90 interaction, promoter recruitment, and ER phosphorylation. F/I decreased estradiol binding and increased Hsp90 association with ER. Chromatin immunoprecipitation revealed that F/I recruited ER to both pS2 and cMyc promoters at earlier times than estradiol, and F/I shifted estradiol recruitment of ER to earlier time points. F/I induced a unique ER phosphorylation profile (increase in serine 305 and decrease in serine 118 phosphorylation) that was distinct from estradiol and estradiol + F/I. Taken together, F/I signaling through PKA selectively regulates estradiol-dependent genes in breast cancer, which is associated with reduced ligand binding and changes in promoter interaction and ER phosphorylation.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Fulvestrant

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