Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin
Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients....
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description | Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR- TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients. |
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Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR- TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.8274</identifier><identifier>PMID: 27015557</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Androgen Antagonists - pharmacology ; Apoptosis - drug effects ; Biomarkers, Tumor - metabolism ; Cell Proliferation - drug effects ; Female ; Humans ; Immunomodulation ; Immunotherapy ; Osteoprotegerin - metabolism ; Phenylthiohydantoin - analogs & derivatives ; Phenylthiohydantoin - pharmacology ; Receptors, Androgen - chemistry ; Receptors, Androgen - metabolism ; Research Paper ; T-Lymphocytes, Cytotoxic - immunology ; Triple Negative Breast Neoplasms - drug therapy ; Triple Negative Breast Neoplasms - immunology ; Triple Negative Breast Neoplasms - metabolism ; Triple Negative Breast Neoplasms - pathology ; Tumor Cells, Cultured</subject><ispartof>Oncotarget, 2016-04, Vol.7 (17), p.23498-23511</ispartof><rights>Copyright: © 2016 Kwilas et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-f6d10c4f509aa4a63252ca05144cc742567746b03c012d746a73815a49e5fc7b3</citedby><cites>FETCH-LOGICAL-c354t-f6d10c4f509aa4a63252ca05144cc742567746b03c012d746a73815a49e5fc7b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029642/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029642/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27015557$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kwilas, Anna R</creatorcontrib><creatorcontrib>Ardiani, Andressa</creatorcontrib><creatorcontrib>Gameiro, Sofia R</creatorcontrib><creatorcontrib>Richards, Jacob</creatorcontrib><creatorcontrib>Hall, Ashley B</creatorcontrib><creatorcontrib>Hodge, James W</creatorcontrib><title>Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR- TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients.</description><subject>Androgen Antagonists - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell Proliferation - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>Immunomodulation</subject><subject>Immunotherapy</subject><subject>Osteoprotegerin - metabolism</subject><subject>Phenylthiohydantoin - analogs & derivatives</subject><subject>Phenylthiohydantoin - pharmacology</subject><subject>Receptors, Androgen - chemistry</subject><subject>Receptors, Androgen - metabolism</subject><subject>Research Paper</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>Triple Negative Breast Neoplasms - drug therapy</subject><subject>Triple Negative Breast Neoplasms - immunology</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><subject>Tumor Cells, Cultured</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1v1TAQtBCIVqV3TshHLin-jJMLUlXxJVXiAmdrn7PJM0rsYDtPevwifiYury3FB3ulnZ0Z7xDymrMr3rVSvIvBxQJpwnLVCaOekXPeq74RWsvnT-ozcpnzD1aPVqYT_UtyJgzjWmtzTn5fhyHFCQMdcE3-AMXHQMseE6xHmjFkX_wvzLQkv85IA04VckC6Swi5UAfBYaIO57liIvXLsgVsFhw8FBzofMy-NvYpbtOewoNYQodriYn6UHWxXqHQJQ7bfDIQRxpzwbimWHDC5MMr8mKEOePl_XtBvn_88O3mc3P79dOXm-vbxkmtSjO2A2dOjZr1AArqmrRwwDRXyjmjhG6NUe2OSce4GGoJRnZcg-pRj87s5AV5f-Jdt139havGEsy27maBdLQRvP2_E_zeTvFgNRN9q0QleHtPkOLPDXOxi893-4GAccuWd6yTRnVMVig7QV2KOSccH2U4s38ztv8ytncZ15E3T-09DjwkKv8AzXSsFg</recordid><startdate>20160426</startdate><enddate>20160426</enddate><creator>Kwilas, Anna R</creator><creator>Ardiani, Andressa</creator><creator>Gameiro, Sofia R</creator><creator>Richards, Jacob</creator><creator>Hall, Ashley B</creator><creator>Hodge, James W</creator><general>Impact Journals LLC</general><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><scope>5PM</scope></search><sort><creationdate>20160426</creationdate><title>Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin</title><author>Kwilas, Anna R ; Ardiani, Andressa ; Gameiro, Sofia R ; Richards, Jacob ; Hall, Ashley B ; Hodge, James W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-f6d10c4f509aa4a63252ca05144cc742567746b03c012d746a73815a49e5fc7b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Androgen Antagonists - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell Proliferation - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>Immunomodulation</topic><topic>Immunotherapy</topic><topic>Osteoprotegerin - metabolism</topic><topic>Phenylthiohydantoin - analogs & derivatives</topic><topic>Phenylthiohydantoin - pharmacology</topic><topic>Receptors, Androgen - chemistry</topic><topic>Receptors, Androgen - metabolism</topic><topic>Research Paper</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><topic>Triple Negative Breast Neoplasms - drug therapy</topic><topic>Triple Negative Breast Neoplasms - immunology</topic><topic>Triple Negative Breast Neoplasms - metabolism</topic><topic>Triple Negative Breast Neoplasms - pathology</topic><topic>Tumor Cells, Cultured</topic><toplevel>online_resources</toplevel><creatorcontrib>Kwilas, Anna R</creatorcontrib><creatorcontrib>Ardiani, Andressa</creatorcontrib><creatorcontrib>Gameiro, Sofia R</creatorcontrib><creatorcontrib>Richards, Jacob</creatorcontrib><creatorcontrib>Hall, Ashley B</creatorcontrib><creatorcontrib>Hodge, James W</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kwilas, Anna R</au><au>Ardiani, Andressa</au><au>Gameiro, Sofia R</au><au>Richards, Jacob</au><au>Hall, Ashley B</au><au>Hodge, James W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-04-26</date><risdate>2016</risdate><volume>7</volume><issue>17</issue><spage>23498</spage><epage>23511</epage><pages>23498-23511</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR- TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>27015557</pmid><doi>10.18632/oncotarget.8274</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Androgen Antagonists - pharmacology Apoptosis - drug effects Biomarkers, Tumor - metabolism Cell Proliferation - drug effects Female Humans Immunomodulation Immunotherapy Osteoprotegerin - metabolism Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - pharmacology Receptors, Androgen - chemistry Receptors, Androgen - metabolism Research Paper T-Lymphocytes, Cytotoxic - immunology Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - immunology Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - pathology Tumor Cells, Cultured |
title | Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin |
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