Hormone-Refractory Breast Cancer Remains Sensitive to the Antitumor Activity of Heat Shock Protein 90 Inhibitors
Purpose: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp)...
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| Veröffentlicht in: | Clinical cancer research 2003-10, Vol.9 (13), p.4961-4971 |
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| creator | BELIAKOFF, Jason BAGATELL, Rochelle PAINE-MURRIETA, Gillian TAYLOR, Charles W LYKKESFELDT, Anne E WHITESELL, Luke |
| description | Purpose: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades.
Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the
molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore,
we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting
the function of Hsp90.
Experimental Design: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin
(17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts.
Results: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1.
Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented
with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining
and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration
also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear,
but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex.
Conclusions: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG
may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored
further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit
the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity. |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_71309973</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>71309973</sourcerecordid><originalsourceid>FETCH-LOGICAL-h270t-e875201013f44e7c710ee05eb2553544c68047044d41f70e9bdae9f0068021393</originalsourceid><addsrcrecordid>eNpF0FFLwzAQB_AiipvTryB5UXwpXJpkaR_nUDcYKJs-lzS72uiazCRV9u2tbuLTHcePP8f_KBlSIWTKsrE47neQeQqcZYPkLIQ3AMop8NNkQLnIKZN0mGxnzrfOYrrE2isdnd-RW48qRDJVVqMnS2yVsYGs0AYTzSeS6EhskExsNLFrnScT3d9N3BFXkxmqSFaN0-_kybuIxpICyNw2pjJ9ejhPTmq1CXhxmKPk5f7ueTpLF48P8-lkkTaZhJhiLkUGFCirOUepJQVEEFhlQjDBuR7nwCVwvua0loBFtVZY1AD9PaOsYKPkep-79e6jwxDL1gSNm42y6LpQSsqgKCTr4eUBdlWL63LrTav8rvzrqAdXB6CCVpu-JqtN-Hci6z_Nf9zN3jXmtfkyHkv926DHgMrrpixKykpejCn7Bhfxfbc</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>71309973</pqid></control><display><type>article</type><title>Hormone-Refractory Breast Cancer Remains Sensitive to the Antitumor Activity of Heat Shock Protein 90 Inhibitors</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>Alma/SFX Local Collection</source><source>EZB Electronic Journals Library</source><creator>BELIAKOFF, Jason ; BAGATELL, Rochelle ; PAINE-MURRIETA, Gillian ; TAYLOR, Charles W ; LYKKESFELDT, Anne E ; WHITESELL, Luke</creator><creatorcontrib>BELIAKOFF, Jason ; BAGATELL, Rochelle ; PAINE-MURRIETA, Gillian ; TAYLOR, Charles W ; LYKKESFELDT, Anne E ; WHITESELL, Luke</creatorcontrib><description>Purpose: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades.
Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the
molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore,
we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting
the function of Hsp90.
Experimental Design: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin
(17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts.
Results: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1.
Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented
with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining
and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration
also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear,
but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex.
Conclusions: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG
may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored
further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit
the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 14581371</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antibiotics, Antineoplastic - pharmacology ; Antineoplastic agents ; Benzoquinones ; Biological and medical sciences ; Breast Neoplasms - drug therapy ; Cell Line, Tumor ; Chemotherapy ; Collagen - pharmacology ; Drug Combinations ; Estrogens - metabolism ; Genes, Reporter ; Hormones - metabolism ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; HSP90 Heat-Shock Proteins - metabolism ; Humans ; Immunoblotting ; Lactams, Macrocyclic ; Laminin - pharmacology ; Lasers ; Ligands ; Medical sciences ; Mice ; Mice, SCID ; Microscopy, Confocal ; Microscopy, Fluorescence ; Neoplasm Transplantation ; Pharmacology. Drug treatments ; Precipitin Tests ; Proteoglycans - pharmacology ; Quinones - pharmacology ; Receptors, Estrogen - metabolism ; Rifabutin - analogs & derivatives ; Rifabutin - pharmacology ; Signal Transduction ; Time Factors ; Transcriptional Activation</subject><ispartof>Clinical cancer research, 2003-10, Vol.9 (13), p.4961-4971</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15252081$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14581371$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>BELIAKOFF, Jason</creatorcontrib><creatorcontrib>BAGATELL, Rochelle</creatorcontrib><creatorcontrib>PAINE-MURRIETA, Gillian</creatorcontrib><creatorcontrib>TAYLOR, Charles W</creatorcontrib><creatorcontrib>LYKKESFELDT, Anne E</creatorcontrib><creatorcontrib>WHITESELL, Luke</creatorcontrib><title>Hormone-Refractory Breast Cancer Remains Sensitive to the Antitumor Activity of Heat Shock Protein 90 Inhibitors</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades.
Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the
molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore,
we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting
the function of Hsp90.
Experimental Design: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin
(17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts.
Results: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1.
Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented
with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining
and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration
also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear,
but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex.
Conclusions: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG
may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored
further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit
the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.</description><subject>Animals</subject><subject>Antibiotics, Antineoplastic - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Benzoquinones</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Collagen - pharmacology</subject><subject>Drug Combinations</subject><subject>Estrogens - metabolism</subject><subject>Genes, Reporter</subject><subject>Hormones - metabolism</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Lactams, Macrocyclic</subject><subject>Laminin - pharmacology</subject><subject>Lasers</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Microscopy, Confocal</subject><subject>Microscopy, Fluorescence</subject><subject>Neoplasm Transplantation</subject><subject>Pharmacology. Drug treatments</subject><subject>Precipitin Tests</subject><subject>Proteoglycans - pharmacology</subject><subject>Quinones - pharmacology</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Rifabutin - analogs & derivatives</subject><subject>Rifabutin - pharmacology</subject><subject>Signal Transduction</subject><subject>Time Factors</subject><subject>Transcriptional Activation</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0FFLwzAQB_AiipvTryB5UXwpXJpkaR_nUDcYKJs-lzS72uiazCRV9u2tbuLTHcePP8f_KBlSIWTKsrE47neQeQqcZYPkLIQ3AMop8NNkQLnIKZN0mGxnzrfOYrrE2isdnd-RW48qRDJVVqMnS2yVsYGs0AYTzSeS6EhskExsNLFrnScT3d9N3BFXkxmqSFaN0-_kybuIxpICyNw2pjJ9ejhPTmq1CXhxmKPk5f7ueTpLF48P8-lkkTaZhJhiLkUGFCirOUepJQVEEFhlQjDBuR7nwCVwvua0loBFtVZY1AD9PaOsYKPkep-79e6jwxDL1gSNm42y6LpQSsqgKCTr4eUBdlWL63LrTav8rvzrqAdXB6CCVpu-JqtN-Hci6z_Nf9zN3jXmtfkyHkv926DHgMrrpixKykpejCn7Bhfxfbc</recordid><startdate>20031015</startdate><enddate>20031015</enddate><creator>BELIAKOFF, Jason</creator><creator>BAGATELL, Rochelle</creator><creator>PAINE-MURRIETA, Gillian</creator><creator>TAYLOR, Charles W</creator><creator>LYKKESFELDT, Anne E</creator><creator>WHITESELL, Luke</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20031015</creationdate><title>Hormone-Refractory Breast Cancer Remains Sensitive to the Antitumor Activity of Heat Shock Protein 90 Inhibitors</title><author>BELIAKOFF, Jason ; BAGATELL, Rochelle ; PAINE-MURRIETA, Gillian ; TAYLOR, Charles W ; LYKKESFELDT, Anne E ; WHITESELL, Luke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h270t-e875201013f44e7c710ee05eb2553544c68047044d41f70e9bdae9f0068021393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antibiotics, Antineoplastic - pharmacology</topic><topic>Antineoplastic agents</topic><topic>Benzoquinones</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Collagen - pharmacology</topic><topic>Drug Combinations</topic><topic>Estrogens - metabolism</topic><topic>Genes, Reporter</topic><topic>Hormones - metabolism</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Lactams, Macrocyclic</topic><topic>Laminin - pharmacology</topic><topic>Lasers</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Microscopy, Confocal</topic><topic>Microscopy, Fluorescence</topic><topic>Neoplasm Transplantation</topic><topic>Pharmacology. Drug treatments</topic><topic>Precipitin Tests</topic><topic>Proteoglycans - pharmacology</topic><topic>Quinones - pharmacology</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Rifabutin - analogs & derivatives</topic><topic>Rifabutin - pharmacology</topic><topic>Signal Transduction</topic><topic>Time Factors</topic><topic>Transcriptional Activation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BELIAKOFF, Jason</creatorcontrib><creatorcontrib>BAGATELL, Rochelle</creatorcontrib><creatorcontrib>PAINE-MURRIETA, Gillian</creatorcontrib><creatorcontrib>TAYLOR, Charles W</creatorcontrib><creatorcontrib>LYKKESFELDT, Anne E</creatorcontrib><creatorcontrib>WHITESELL, Luke</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BELIAKOFF, Jason</au><au>BAGATELL, Rochelle</au><au>PAINE-MURRIETA, Gillian</au><au>TAYLOR, Charles W</au><au>LYKKESFELDT, Anne E</au><au>WHITESELL, Luke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hormone-Refractory Breast Cancer Remains Sensitive to the Antitumor Activity of Heat Shock Protein 90 Inhibitors</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2003-10-15</date><risdate>2003</risdate><volume>9</volume><issue>13</issue><spage>4961</spage><epage>4971</epage><pages>4961-4971</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades.
Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the
molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore,
we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting
the function of Hsp90.
Experimental Design: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin
(17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts.
Results: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1.
Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented
with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining
and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration
also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear,
but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex.
Conclusions: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG
may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored
further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit
the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>14581371</pmid><tpages>11</tpages></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; Alma/SFX Local Collection; EZB Electronic Journals Library |
| subjects | Animals Antibiotics, Antineoplastic - pharmacology Antineoplastic agents Benzoquinones Biological and medical sciences Breast Neoplasms - drug therapy Cell Line, Tumor Chemotherapy Collagen - pharmacology Drug Combinations Estrogens - metabolism Genes, Reporter Hormones - metabolism HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - metabolism Humans Immunoblotting Lactams, Macrocyclic Laminin - pharmacology Lasers Ligands Medical sciences Mice Mice, SCID Microscopy, Confocal Microscopy, Fluorescence Neoplasm Transplantation Pharmacology. Drug treatments Precipitin Tests Proteoglycans - pharmacology Quinones - pharmacology Receptors, Estrogen - metabolism Rifabutin - analogs & derivatives Rifabutin - pharmacology Signal Transduction Time Factors Transcriptional Activation |
| title | Hormone-Refractory Breast Cancer Remains Sensitive to the Antitumor Activity of Heat Shock Protein 90 Inhibitors |
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