Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer
Using a novel approach that detects changes in the conformation of ERα, we studied the efficacy of anti-estrogens to inactivate ERα under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERα by protein kinase A (PKA) induced resistance to tamoxifen...
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| Veröffentlicht in: | Cancer cell 2004-06, Vol.5 (6), p.597-605 |
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| creator | Michalides, Rob Griekspoor, Alexander Balkenende, Astrid Verwoerd, Desiree Janssen, Lennert Jalink, Kees Floore, Arno Velds, Arno van `t Veer, Laura Neefjes, Jacques |
| description | Using a novel approach that detects changes in the conformation of ERα, we studied the efficacy of anti-estrogens to inactivate ERα under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERα by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERα-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERα. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIα, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIα converts tamoxifen from an ERα inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant). |
| doi_str_mv | 10.1016/j.ccr.2004.05.016 |
| format | Article |
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We show that phosphorylation of serine-305 in the hinge region of ERα by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERα-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERα. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIα, was associated with tamoxifen resistance prior to treatment. 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We show that phosphorylation of serine-305 in the hinge region of ERα by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERα-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERα. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIα, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIα converts tamoxifen from an ERα inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).</description><subject>Antineoplastic Agents, Hormonal - pharmacology</subject><subject>Binding Sites</subject><subject>Blotting, Western</subject><subject>Breast Neoplasms - enzymology</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Division</subject><subject>Cell Line, Tumor</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Down-Regulation</subject><subject>Drug Resistance, Neoplasm</subject><subject>Enzyme Activation</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Estradiol - analogs & derivatives</subject><subject>Estradiol - pharmacology</subject><subject>Estrogen Receptor alpha</subject><subject>Estrogen Receptor Modulators - pharmacology</subject><subject>Female</subject><subject>Fluorescence Resonance Energy Transfer</subject><subject>Humans</subject><subject>Luciferases - metabolism</subject><subject>Microscopy, Confocal</subject><subject>Models, Biological</subject><subject>Nucleic Acid Hybridization</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Phosphorylation</subject><subject>Protein Conformation</subject><subject>Protein Structure, Tertiary</subject><subject>Receptors, Estrogen - chemistry</subject><subject>Receptors, Estrogen - metabolism</subject><subject>RNA Interference</subject><subject>Serine - chemistry</subject><subject>Tamoxifen - pharmacology</subject><subject>Time Factors</subject><subject>Transcriptional Activation</subject><subject>Transfection</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1OHDEUhK2IKBCSA7BBXrHrju1uu91ihRD5UZCSBVlbz-5n8Gi6PdgeFI6Vi-RM8TAjscvKpdJXJb8i5IyzljOuPq1a51IrGOtbJtvqvCEnXA-66ZRWR1XLTjaKM31M3ue8YpXgw_iOHHPJx04ocUIe72COv4PHhSbMIRdYHFL7TIG6uPiYZighLrCmkCpQaPS0PCCtMsX7l5TDTYmJ_v1DwRdM9Of3KwquhKeXJA0LtQmhRt2uO30gbz2sM348vKfk1-ebu-uvze2PL9-ur24b142iNHJiMGihlQKp-0nIHsahnzo7atDeWjH0Q68kTKPnFq1XznKJVVfX9Yx3p-Ri37tJ8XFb_2vmkB2u17Bg3GYzCMalEKyCfA-6FHNO6M0mhRnSs-HM7HY2K1N3NrudDZOmOjVzfijf2hmn18Rh2Apc7gGsJz4FTCa7gPX-KdTFipli-E_9P0E_j90</recordid><startdate>20040601</startdate><enddate>20040601</enddate><creator>Michalides, Rob</creator><creator>Griekspoor, Alexander</creator><creator>Balkenende, Astrid</creator><creator>Verwoerd, Desiree</creator><creator>Janssen, Lennert</creator><creator>Jalink, Kees</creator><creator>Floore, Arno</creator><creator>Velds, Arno</creator><creator>van `t Veer, Laura</creator><creator>Neefjes, Jacques</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20040601</creationdate><title>Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer</title><author>Michalides, Rob ; Griekspoor, Alexander ; Balkenende, Astrid ; Verwoerd, Desiree ; Janssen, Lennert ; Jalink, Kees ; Floore, Arno ; Velds, Arno ; van `t Veer, Laura ; Neefjes, Jacques</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c392t-5d0a782866a584d254a974d3b98a8fbb2747465ad9f1bebf6cb15ef1b746c4013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Antineoplastic Agents, Hormonal - pharmacology</topic><topic>Binding Sites</topic><topic>Blotting, Western</topic><topic>Breast Neoplasms - enzymology</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Division</topic><topic>Cell Line, Tumor</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Down-Regulation</topic><topic>Drug Resistance, Neoplasm</topic><topic>Enzyme Activation</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Estradiol - analogs & derivatives</topic><topic>Estradiol - pharmacology</topic><topic>Estrogen Receptor alpha</topic><topic>Estrogen Receptor Modulators - pharmacology</topic><topic>Female</topic><topic>Fluorescence Resonance Energy Transfer</topic><topic>Humans</topic><topic>Luciferases - metabolism</topic><topic>Microscopy, Confocal</topic><topic>Models, Biological</topic><topic>Nucleic Acid Hybridization</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Phosphorylation</topic><topic>Protein Conformation</topic><topic>Protein Structure, Tertiary</topic><topic>Receptors, Estrogen - chemistry</topic><topic>Receptors, Estrogen - metabolism</topic><topic>RNA Interference</topic><topic>Serine - chemistry</topic><topic>Tamoxifen - pharmacology</topic><topic>Time Factors</topic><topic>Transcriptional Activation</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Michalides, Rob</creatorcontrib><creatorcontrib>Griekspoor, Alexander</creatorcontrib><creatorcontrib>Balkenende, Astrid</creatorcontrib><creatorcontrib>Verwoerd, Desiree</creatorcontrib><creatorcontrib>Janssen, Lennert</creatorcontrib><creatorcontrib>Jalink, Kees</creatorcontrib><creatorcontrib>Floore, Arno</creatorcontrib><creatorcontrib>Velds, Arno</creatorcontrib><creatorcontrib>van `t Veer, Laura</creatorcontrib><creatorcontrib>Neefjes, Jacques</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Michalides, Rob</au><au>Griekspoor, Alexander</au><au>Balkenende, Astrid</au><au>Verwoerd, Desiree</au><au>Janssen, Lennert</au><au>Jalink, Kees</au><au>Floore, Arno</au><au>Velds, Arno</au><au>van `t Veer, Laura</au><au>Neefjes, Jacques</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2004-06-01</date><risdate>2004</risdate><volume>5</volume><issue>6</issue><spage>597</spage><epage>605</epage><pages>597-605</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Using a novel approach that detects changes in the conformation of ERα, we studied the efficacy of anti-estrogens to inactivate ERα under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERα by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERα-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERα. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIα, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIα converts tamoxifen from an ERα inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15193262</pmid><doi>10.1016/j.ccr.2004.05.016</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer cell, 2004-06, Vol.5 (6), p.597-605 |
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| source | Electronic Journals Library; MEDLINE; Elsevier ScienceDirect Journals Complete; Cell Press Free Archives (Open Access) |
| subjects | Antineoplastic Agents, Hormonal - pharmacology Binding Sites Blotting, Western Breast Neoplasms - enzymology Breast Neoplasms - 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 Estradiol - pharmacology Estrogen Receptor alpha Estrogen Receptor Modulators - pharmacology Female Fluorescence Resonance Energy Transfer Humans Luciferases - metabolism Microscopy, Confocal Models, Biological Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis Phosphorylation Protein Conformation Protein Structure, Tertiary Receptors, Estrogen - chemistry Receptors, Estrogen - metabolism RNA Interference Serine - chemistry Tamoxifen - pharmacology Time Factors Transcriptional Activation Transfection |
| title | Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer |
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