Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis
Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular...
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| Veröffentlicht in: | Nature 2005-12, Vol.438 (7070), p.981-987 |
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| description | Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene,
PAX2
, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that
PAX2
is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the
PAX2
promoter.
The tamoxifen paradox
Why tamoxifen serves as a treatment for breast cancer but increases the incidence of endometrial cancer is of great importance both scientifically and practically. Analysis of targets common to both tamoxifen and oestrogen points to the PAX2 transcription factor as a key to the phenomenon. PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium. The identification of PAX2 as mediator of the carcinogenic activity of both oestrogen and tamoxifen in the uterus may provide useful information for the design of safer drugs for the treatment of breast cancer and endometrial cancer. |
| doi_str_mv | 10.1038/nature04225 |
| format | Article |
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PAX2
, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that
PAX2
is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the
PAX2
promoter.
The tamoxifen paradox
Why tamoxifen serves as a treatment for breast cancer but increases the incidence of endometrial cancer is of great importance both scientifically and practically. Analysis of targets common to both tamoxifen and oestrogen points to the PAX2 transcription factor as a key to the phenomenon. PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium. The identification of PAX2 as mediator of the carcinogenic activity of both oestrogen and tamoxifen in the uterus may provide useful information for the design of safer drugs for the treatment of breast cancer and endometrial cancer.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/nature04225</identifier><identifier>PMID: 16355216</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Biological and medical sciences ; Breast cancer ; Carcinogenesis ; Carcinogens ; Cell Proliferation - drug effects ; Cell Transformation, Neoplastic - drug effects ; Cell Transformation, Neoplastic - pathology ; DNA Methylation - drug effects ; Endometrial cancer ; Endometrial Neoplasms - chemically induced ; Endometrial Neoplasms - pathology ; Endometrium - drug effects ; Endometrium - pathology ; Estrogen Receptor alpha - metabolism ; Estrogens ; Female ; Female genital diseases ; Genetics ; Gynecology ; Gynecology. Andrology. Obstetrics ; Humanities and Social Sciences ; Humans ; Medical sciences ; Medical treatment ; Mice ; Mice, Nude ; multidisciplinary ; Oligonucleotide Array Sequence Analysis ; PAX2 Transcription Factor - genetics ; PAX2 Transcription Factor - metabolism ; Promoter Regions, Genetic - genetics ; Science ; Science (multidisciplinary) ; Selective Estrogen Receptor Modulators - adverse effects ; Selective Estrogen Receptor Modulators - pharmacology ; Tamoxifen - adverse effects ; Tamoxifen - pharmacology ; Tumors</subject><ispartof>Nature, 2005-12, Vol.438 (7070), p.981-987</ispartof><rights>Springer Nature Limited 2005</rights><rights>2006 INIST-CNRS</rights><rights>COPYRIGHT 2005 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Dec 15, 2005</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c716t-34dd49ebe2c6534c27cea10444644dd074c9bb1cb41e8b8efe2b29e7d5099df93</citedby><cites>FETCH-LOGICAL-c716t-34dd49ebe2c6534c27cea10444644dd074c9bb1cb41e8b8efe2b29e7d5099df93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature04225$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature04225$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17346751$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16355216$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Huijian</creatorcontrib><creatorcontrib>Chen, Yupeng</creatorcontrib><creatorcontrib>Liang, Jing</creatorcontrib><creatorcontrib>Shi, Bin</creatorcontrib><creatorcontrib>Wu, Ge</creatorcontrib><creatorcontrib>Zhang, Ying</creatorcontrib><creatorcontrib>Wang, Dan</creatorcontrib><creatorcontrib>Li, Ruifang</creatorcontrib><creatorcontrib>Yi, Xia</creatorcontrib><creatorcontrib>Zhang, Hua</creatorcontrib><creatorcontrib>Sun, Luyang</creatorcontrib><creatorcontrib>Shang, Yongfeng</creatorcontrib><title>Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis</title><title>Nature</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene,
PAX2
, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that
PAX2
is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the
PAX2
promoter.
The tamoxifen paradox
Why tamoxifen serves as a treatment for breast cancer but increases the incidence of endometrial cancer is of great importance both scientifically and practically. Analysis of targets common to both tamoxifen and oestrogen points to the PAX2 transcription factor as a key to the phenomenon. PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium. The identification of PAX2 as mediator of the carcinogenic activity of both oestrogen and tamoxifen in the uterus may provide useful information for the design of safer drugs for the treatment of breast cancer and endometrial cancer.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Breast cancer</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Transformation, Neoplastic - drug effects</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>DNA Methylation - drug effects</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - chemically induced</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Endometrium - drug effects</subject><subject>Endometrium - pathology</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Estrogens</subject><subject>Female</subject><subject>Female genital diseases</subject><subject>Genetics</subject><subject>Gynecology</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Medical treatment</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>multidisciplinary</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>PAX2 Transcription Factor - genetics</subject><subject>PAX2 Transcription Factor - metabolism</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Selective Estrogen Receptor Modulators - adverse effects</subject><subject>Selective Estrogen Receptor Modulators - pharmacology</subject><subject>Tamoxifen - adverse effects</subject><subject>Tamoxifen - pharmacology</subject><subject>Tumors</subject><issn>0028-0836</issn><issn>1476-4687</issn><issn>1476-4679</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0l1r1EAUBuAgil1br7yXIFSUmjrfk1wui9pCsaIVvQuTyck6NZnZzkyk---d7S5sV1YlF4GZ57whLyfLnmF0ihEt31oVRw-IEcIfZBPMpCiYKOXDbIIQKQtUUnGQPQnhGiHEsWSPswMsKOcEi0nWnC0XboD4Y9mraJwtemN_QpsrHc2vu5Pcdfmn6XeSD9AaFSHkUQ3u1nRgixDNMKbBNAC2XeV4o_pcK6-NdXOwEEw4yh51qg_wdPM-zL6-f3c1OysuLj-cz6YXhZZYxIKytmUVNEC04JRpIjUojBhjgqUrJJmumgbrhmEomxI6IA2pQLYcVVXbVfQwe7nOXXh3M0KI9WCChr5XFtwYalIiVFFa_hfiKlVGOErw1b9h6plyStEq88Uf9NqN3qb_rQliXCApZULFGs1VD7WxnYte6VVNXvXOQmfS8RSXnAlBRLUN3fF6YW7q--h0D0pPC4PRe1Nf7wwkE-E2ztUYQn3-5fOuPfm7nV59m33cq7V3IXjo6oU3g_LLGqN6tav1vV1N-vmmsrFJu7W1m-VM4HgDVNCq77yy2oStk5QJyXFyb9YupCs7B7_tft93fwMX5_6V</recordid><startdate>20051215</startdate><enddate>20051215</enddate><creator>Wu, Huijian</creator><creator>Chen, Yupeng</creator><creator>Liang, Jing</creator><creator>Shi, Bin</creator><creator>Wu, Ge</creator><creator>Zhang, Ying</creator><creator>Wang, Dan</creator><creator>Li, Ruifang</creator><creator>Yi, Xia</creator><creator>Zhang, Hua</creator><creator>Sun, Luyang</creator><creator>Shang, Yongfeng</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</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>ATWCN</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7U7</scope><scope>7U5</scope><scope>L7M</scope></search><sort><creationdate>20051215</creationdate><title>Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis</title><author>Wu, Huijian ; Chen, Yupeng ; Liang, Jing ; Shi, Bin ; Wu, Ge ; Zhang, Ying ; Wang, Dan ; Li, Ruifang ; Yi, Xia ; Zhang, Hua ; Sun, Luyang ; Shang, Yongfeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c716t-34dd49ebe2c6534c27cea10444644dd074c9bb1cb41e8b8efe2b29e7d5099df93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Breast cancer</topic><topic>Carcinogenesis</topic><topic>Carcinogens</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Transformation, Neoplastic - drug effects</topic><topic>Cell Transformation, Neoplastic - pathology</topic><topic>DNA Methylation - drug effects</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - chemically induced</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Endometrium - drug effects</topic><topic>Endometrium - pathology</topic><topic>Estrogen Receptor alpha - metabolism</topic><topic>Estrogens</topic><topic>Female</topic><topic>Female genital diseases</topic><topic>Genetics</topic><topic>Gynecology</topic><topic>Gynecology. 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Obstetrics</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Medical treatment</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>multidisciplinary</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>PAX2 Transcription Factor - genetics</topic><topic>PAX2 Transcription Factor - metabolism</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Selective Estrogen Receptor Modulators - adverse effects</topic><topic>Selective Estrogen Receptor Modulators - pharmacology</topic><topic>Tamoxifen - adverse effects</topic><topic>Tamoxifen - pharmacology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Huijian</creatorcontrib><creatorcontrib>Chen, Yupeng</creatorcontrib><creatorcontrib>Liang, Jing</creatorcontrib><creatorcontrib>Shi, 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Aerospace</collection><jtitle>Nature</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Huijian</au><au>Chen, Yupeng</au><au>Liang, Jing</au><au>Shi, Bin</au><au>Wu, Ge</au><au>Zhang, Ying</au><au>Wang, Dan</au><au>Li, Ruifang</au><au>Yi, Xia</au><au>Zhang, Hua</au><au>Sun, Luyang</au><au>Shang, Yongfeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis</atitle><jtitle>Nature</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2005-12-15</date><risdate>2005</risdate><volume>438</volume><issue>7070</issue><spage>981</spage><epage>987</epage><pages>981-987</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><eissn>1476-4679</eissn><coden>NATUAS</coden><abstract>Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene,
PAX2
, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that
PAX2
is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the
PAX2
promoter.
The tamoxifen paradox
Why tamoxifen serves as a treatment for breast cancer but increases the incidence of endometrial cancer is of great importance both scientifically and practically. Analysis of targets common to both tamoxifen and oestrogen points to the PAX2 transcription factor as a key to the phenomenon. PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium. The identification of PAX2 as mediator of the carcinogenic activity of both oestrogen and tamoxifen in the uterus may provide useful information for the design of safer drugs for the treatment of breast cancer and endometrial cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>16355216</pmid><doi>10.1038/nature04225</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature, 2005-12, Vol.438 (7070), p.981-987 |
| issn | 0028-0836 1476-4687 1476-4679 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_28009338 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | Animals Biological and medical sciences Breast cancer Carcinogenesis Carcinogens Cell Proliferation - drug effects Cell Transformation, Neoplastic - drug effects Cell Transformation, Neoplastic - pathology DNA Methylation - drug effects Endometrial cancer Endometrial Neoplasms - chemically induced Endometrial Neoplasms - pathology Endometrium - drug effects Endometrium - pathology Estrogen Receptor alpha - metabolism Estrogens Female Female genital diseases Genetics Gynecology Gynecology. Andrology. Obstetrics Humanities and Social Sciences Humans Medical sciences Medical treatment Mice Mice, Nude multidisciplinary Oligonucleotide Array Sequence Analysis PAX2 Transcription Factor - genetics PAX2 Transcription Factor - metabolism Promoter Regions, Genetic - genetics Science Science (multidisciplinary) Selective Estrogen Receptor Modulators - adverse effects Selective Estrogen Receptor Modulators - pharmacology Tamoxifen - adverse effects Tamoxifen - pharmacology Tumors |
| title | Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T11%3A13%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hypomethylation-linked%20activation%20of%20PAX2%20mediates%20tamoxifen-stimulated%20endometrial%20carcinogenesis&rft.jtitle=Nature&rft.au=Wu,%20Huijian&rft.date=2005-12-15&rft.volume=438&rft.issue=7070&rft.spage=981&rft.epage=987&rft.pages=981-987&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature04225&rft_dat=%3Cgale_proqu%3EA185466269%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=204560777&rft_id=info:pmid/16355216&rft_galeid=A185466269&rfr_iscdi=true |