title: PKA-induced resistance to tamoxifen is associated with an altered orientation of ERalpha towards co-activator SRC-1.
abstract: Resistance to tamoxifen is observed in half of the recurrences in breast cancer, where the anti-estrogen tamoxifen acquires agonistic properties for transactivating estrogen receptor alpha (ERalpha). In a previous study, we showed that protein kinase A (PKA)-mediated phosphorylation of serine 305 (S305) of ERalpha results in resistance to tamoxifen. Now, we demonstrate that phosphorylation of S305 in ERalpha by PKA leads to an altered orientation between ERalpha and its coactivator SRC-1, which renders the transcription complex active in the presence of tamoxifen. This altered orientation involves the C-termini of ERalpha and SRC-1, which required a prolonged AF-1-mediated interaction. This intermolecular reorientation as a result of PKA-mediated phosphorylation of ERalpha-S305 and tamoxifen binding provides a unique model for resistance to the anticancer drug tamoxifen.
authors.affiliation: Department of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.forename: Alexander
authors.initials: A
authors.lastname: Griekspoor
authors.forename: Valeria
authors.initials: V
authors.lastname: Berno
authors.forename: Kim
authors.initials: K
authors.lastname: Lakeman
authors.forename: Kees
authors.initials: K
authors.lastname: Jalink
authors.forename: Michael
authors.initials: M
authors.lastname: Mancini
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.forename: Rob
authors.initials: R
authors.lastname: Michalides
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D056920:Nuclear Receptor Coactivator 1; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D014157:Transcription Factors; D013629:Tamoxifen; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D017868:Cyclic AMP-Dependent Protein Kinases