Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance
Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2017-01, Vol.355 (6320), p.78-83 |
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| creator | Ku, Sheng Yu Rosario, Spencer Wang, Yanqing Mu, Ping Seshadri, Mukund Goodrich, Zachary W. Goodrich, Maxwell M. Labbé, David P. Gomez, Eduardo Cortes Wang, Jianmin Long, Henry W. Xu, Bo Brown, Myles Loda, Massimo Sawyers, Charles L. Ellis, Leigh Goodrich, David W. |
| description | Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy. |
| doi_str_mv | 10.1126/science.aah4199 |
| format | Article |
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The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aah4199</identifier><identifier>PMID: 28059767</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adenocarcinoma - secondary ; Androgen Antagonists - therapeutic use ; Androgen receptors ; Androgens ; Animals ; Cancer ; Cell Line, Tumor ; Cell Lineage ; Cell Plasticity ; Deprivation ; Drug resistance ; Drug Resistance, Neoplasm - genetics ; Drugs ; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors ; Enhancer of Zeste Homolog 2 Protein - genetics ; Epigenesis, Genetic ; Epigenetics ; Gene expression ; Histology ; Hormones ; Humans ; Inhibitors ; Male ; Metastasis ; Mice ; Mutation ; Mutations ; Neoplasm Metastasis ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - genetics ; Neoplasms, Experimental - pathology ; Neuroendocrine Tumors - drug therapy ; Neuroendocrine Tumors - genetics ; Neuroendocrine Tumors - pathology ; Plastic properties ; Plasticity ; Prostate ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; PTEN Phosphohydrolase - genetics ; Retinoblastoma ; Retinoblastoma-Like Protein p107 - genetics ; Rodents ; Sensitivity ; Signal transduction ; SOXB1 Transcription Factors - antagonists & inhibitors ; SOXB1 Transcription Factors - genetics ; Suppressors ; Switching ; Therapy ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - genetics ; Tumors</subject><ispartof>Science (American Association for the Advancement of Science), 2017-01, Vol.355 (6320), p.78-83</ispartof><rights>Copyright © 2016 American Association for the Advancement of Science</rights><rights>Copyright © 2017, American Association for the Advancement of Science.</rights><rights>Copyright © 2017, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-9390d660c82abfd878586429707b2d20677bc39e8af72ec89027103b342152633</citedby><cites>FETCH-LOGICAL-c476t-9390d660c82abfd878586429707b2d20677bc39e8af72ec89027103b342152633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/24917838$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/24917838$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,776,780,799,881,2871,2872,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28059767$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ku, Sheng Yu</creatorcontrib><creatorcontrib>Rosario, Spencer</creatorcontrib><creatorcontrib>Wang, Yanqing</creatorcontrib><creatorcontrib>Mu, Ping</creatorcontrib><creatorcontrib>Seshadri, Mukund</creatorcontrib><creatorcontrib>Goodrich, Zachary W.</creatorcontrib><creatorcontrib>Goodrich, Maxwell M.</creatorcontrib><creatorcontrib>Labbé, David P.</creatorcontrib><creatorcontrib>Gomez, Eduardo Cortes</creatorcontrib><creatorcontrib>Wang, Jianmin</creatorcontrib><creatorcontrib>Long, Henry W.</creatorcontrib><creatorcontrib>Xu, Bo</creatorcontrib><creatorcontrib>Brown, Myles</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><creatorcontrib>Sawyers, Charles L.</creatorcontrib><creatorcontrib>Ellis, Leigh</creatorcontrib><creatorcontrib>Goodrich, David W.</creatorcontrib><title>Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.</description><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - secondary</subject><subject>Androgen Antagonists - therapeutic use</subject><subject>Androgen receptors</subject><subject>Androgens</subject><subject>Animals</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Cell Lineage</subject><subject>Cell Plasticity</subject><subject>Deprivation</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Drugs</subject><subject>Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors</subject><subject>Enhancer of Zeste Homolog 2 Protein - genetics</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Histology</subject><subject>Hormones</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Male</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mutation</subject><subject>Mutations</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - genetics</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Neuroendocrine Tumors - drug therapy</subject><subject>Neuroendocrine Tumors - genetics</subject><subject>Neuroendocrine Tumors - pathology</subject><subject>Plastic properties</subject><subject>Plasticity</subject><subject>Prostate</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>Retinoblastoma</subject><subject>Retinoblastoma-Like Protein p107 - genetics</subject><subject>Rodents</subject><subject>Sensitivity</subject><subject>Signal transduction</subject><subject>SOXB1 Transcription Factors - antagonists & inhibitors</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>Suppressors</subject><subject>Switching</subject><subject>Therapy</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Protein p53 - 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drug therapy</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - secondary</topic><topic>Androgen Antagonists - therapeutic use</topic><topic>Androgen receptors</topic><topic>Androgens</topic><topic>Animals</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Cell Lineage</topic><topic>Cell Plasticity</topic><topic>Deprivation</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Drugs</topic><topic>Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors</topic><topic>Enhancer of Zeste Homolog 2 Protein - genetics</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Histology</topic><topic>Hormones</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Male</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mutation</topic><topic>Mutations</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - genetics</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Neuroendocrine Tumors - drug therapy</topic><topic>Neuroendocrine Tumors - genetics</topic><topic>Neuroendocrine Tumors - pathology</topic><topic>Plastic properties</topic><topic>Plasticity</topic><topic>Prostate</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - pathology</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>Retinoblastoma</topic><topic>Retinoblastoma-Like Protein p107 - genetics</topic><topic>Rodents</topic><topic>Sensitivity</topic><topic>Signal transduction</topic><topic>SOXB1 Transcription Factors - antagonists & inhibitors</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>Suppressors</topic><topic>Switching</topic><topic>Therapy</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ku, Sheng Yu</creatorcontrib><creatorcontrib>Rosario, Spencer</creatorcontrib><creatorcontrib>Wang, Yanqing</creatorcontrib><creatorcontrib>Mu, Ping</creatorcontrib><creatorcontrib>Seshadri, Mukund</creatorcontrib><creatorcontrib>Goodrich, Zachary W.</creatorcontrib><creatorcontrib>Goodrich, Maxwell M.</creatorcontrib><creatorcontrib>Labbé, David P.</creatorcontrib><creatorcontrib>Gomez, Eduardo Cortes</creatorcontrib><creatorcontrib>Wang, Jianmin</creatorcontrib><creatorcontrib>Long, Henry W.</creatorcontrib><creatorcontrib>Xu, Bo</creatorcontrib><creatorcontrib>Brown, Myles</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><creatorcontrib>Sawyers, Charles L.</creatorcontrib><creatorcontrib>Ellis, Leigh</creatorcontrib><creatorcontrib>Goodrich, David 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>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ku, Sheng Yu</au><au>Rosario, Spencer</au><au>Wang, Yanqing</au><au>Mu, Ping</au><au>Seshadri, Mukund</au><au>Goodrich, Zachary W.</au><au>Goodrich, Maxwell M.</au><au>Labbé, David P.</au><au>Gomez, Eduardo Cortes</au><au>Wang, Jianmin</au><au>Long, Henry W.</au><au>Xu, Bo</au><au>Brown, Myles</au><au>Loda, Massimo</au><au>Sawyers, Charles L.</au><au>Ellis, Leigh</au><au>Goodrich, David W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2017-01-06</date><risdate>2017</risdate><volume>355</volume><issue>6320</issue><spage>78</spage><epage>83</epage><pages>78-83</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>28059767</pmid><doi>10.1126/science.aah4199</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 0036-8075 1095-9203 |
| language | eng |
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| source | American Association for the Advancement of Science; Jstor Complete Legacy; MEDLINE |
| subjects | Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - secondary Androgen Antagonists - therapeutic use Androgen receptors Androgens Animals Cancer Cell Line, Tumor Cell Lineage Cell Plasticity Deprivation Drug resistance Drug Resistance, Neoplasm - genetics Drugs Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors Enhancer of Zeste Homolog 2 Protein - genetics Epigenesis, Genetic Epigenetics Gene expression Histology Hormones Humans Inhibitors Male Metastasis Mice Mutation Mutations Neoplasm Metastasis Neoplasms, Experimental - drug therapy Neoplasms, Experimental - genetics Neoplasms, Experimental - pathology Neuroendocrine Tumors - drug therapy Neuroendocrine Tumors - genetics Neuroendocrine Tumors - pathology Plastic properties Plasticity Prostate Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology PTEN Phosphohydrolase - genetics Retinoblastoma Retinoblastoma-Like Protein p107 - genetics Rodents Sensitivity Signal transduction SOXB1 Transcription Factors - antagonists & inhibitors SOXB1 Transcription Factors - genetics Suppressors Switching Therapy Tumor suppressor genes Tumor Suppressor Protein p53 - genetics Tumors |
| title | Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance |
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