Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer.

Cancer cell ·Vol. 5 ·No. 6 ·2004-06-00 ·Pages 597-605

Michalides R, Griekspoor A, Balkenende A, Verwoerd D, Janssen L, Jalink K, Floore A, Velds A, van't Veer L, Neefjes J

Abstract

Using a novel approach that detects changes in the conformation of ERalpha, we studied the efficacy of anti-estrogens to inactivate ERalpha under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERalpha by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERalpha-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERalpha. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIalpha, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIalpha converts tamoxifen from an ERalpha inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).

MeSH Terms

Antineoplastic Agents, Hormonal/pharmacology Binding Sites Blotting, Western Breast Neoplasms/enzymology,pathology Cell Division Cell Line, Tumor Cyclic AMP-Dependent Protein Kinases/metabolism Down-Regulation Drug Resistance, Neoplasm Enzyme Activation Enzyme Inhibitors/pharmacology Estradiol/analogs & derivatives,pharmacology Estrogen Receptor Modulators/pharmacology Estrogen Receptor alpha Female Fluorescence Resonance Energy Transfer Fulvestrant Humans Luciferases/metabolism Microscopy, Confocal Models, Biological Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis Phosphorylation Protein Conformation Protein Structure, Tertiary RNA Interference Receptors, Estrogen/chemistry,metabolism Serine/chemistry Tamoxifen/pharmacology Time Factors Transcriptional Activation Transfection

Chemicals

Antineoplastic Agents, Hormonal Enzyme Inhibitors Estrogen Receptor Modulators Estrogen Receptor alpha Receptors, Estrogen Tamoxifen Fulvestrant Serine Estradiol Luciferases Cyclic AMP-Dependent Protein Kinases

Authors & Affiliations

10 authors, click to expand affiliations / ORCID

Michalides Rob

Department of Tumor Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Griekspoor Alexander

Balkenende Astrid

Verwoerd Desiree

Janssen Lennert

Jalink Kees

Floore Arno

Velds Arno

van't Veer Laura

Neefjes Jacques

Article Info

Journal

Cancer cell

Abbr.

Cancer Cell

ISSN

1535-6108

DOI

10.1016/j.ccr.2004.05.016

Published

2004-06-00

Pages

597-605

Language

English

Region

United States

NLM ID

101130617

Subset

External Links

PubMed source DOI: 10.1016/j.ccr.2004.05.016 View journal details

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Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer.

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