Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion
Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriche...
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| Veröffentlicht in: | Oncogene 2011-05, Vol.30 (18), p.2161-2172 |
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| creator | Yu, F Li, J Chen, H Fu, J Ray, S Huang, S Zheng, H Ai, W |
| description | Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriched populations in mouse primary mammary tumor and breast cancer cell lines. Knockdown of KLF4 in breast cancer cells (MCF-7 and MDA-MB-231) decreased the proportion of stem/progenitor cells as demonstrated by expression of stem cell surface markers such as aldehyde dehydrogenase 1, side population and by
in vitro
mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation
in vitro
and inhibited tumorigenesis in immunocompromised non-obese diabetic/severe combined immunodeficiency mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 has a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell–like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer. |
| doi_str_mv | 10.1038/onc.2010.591 |
| format | Article |
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in vitro
mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation
in vitro
and inhibited tumorigenesis in immunocompromised non-obese diabetic/severe combined immunodeficiency mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 has a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell–like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2010.591</identifier><identifier>PMID: 21242971</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1347 ; 631/67/395 ; 631/67/71 ; 631/80/84/2336 ; Aldehyde dehydrogenase ; Apoptosis ; Biological and medical sciences ; Breast cancer ; Breast Neoplasms - pathology ; Breast Neoplasms - physiopathology ; Cancer cells ; Cell adhesion & migration ; Cell Biology ; Cell Line, Tumor ; Cell migration ; Cell physiology ; Cell surface ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Colonies ; Development and progression ; Diabetes mellitus ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene Knockdown Techniques ; Gynecology. Andrology. Obstetrics ; Health aspects ; Human Genetics ; Humans ; Internal Medicine ; KLF4 protein ; Krueppel-like factor ; Kruppel-Like Transcription Factors - genetics ; Kruppel-Like Transcription Factors - physiology ; Mammary gland ; Mammary gland diseases ; Medical sciences ; Medicine ; Medicine & Public Health ; Molecular and cellular biology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplastic Stem Cells - cytology ; Notch protein ; Oncogenes ; Oncology ; original-article ; Physiological aspects ; Progenitor cells ; Proteins ; Receptors, Notch - metabolism ; Risk factors ; Severe combined immunodeficiency ; Signal Transduction ; Stem cell transplantation ; Stem cells ; Surface markers ; Transcription factors ; Tumor cell lines ; Tumorigenesis ; Tumorigenicity ; Tumors</subject><ispartof>Oncogene, 2011-05, Vol.30 (18), p.2161-2172</ispartof><rights>Macmillan Publishers Limited 2011</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2011 Nature Publishing Group</rights><rights>Macmillan Publishers Limited 2011.</rights><rights>Copyright Nature Publishing Group May 5, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c631t-3a8f0fc5df821cd1999a985413035739f691dc90974364767eaaeb5c73fe91833</citedby><cites>FETCH-LOGICAL-c631t-3a8f0fc5df821cd1999a985413035739f691dc90974364767eaaeb5c73fe91833</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/onc.2010.591$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2010.591$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,2725,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24143246$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21242971$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, F</creatorcontrib><creatorcontrib>Li, J</creatorcontrib><creatorcontrib>Chen, H</creatorcontrib><creatorcontrib>Fu, J</creatorcontrib><creatorcontrib>Ray, S</creatorcontrib><creatorcontrib>Huang, S</creatorcontrib><creatorcontrib>Zheng, H</creatorcontrib><creatorcontrib>Ai, W</creatorcontrib><title>Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriched populations in mouse primary mammary tumor and breast cancer cell lines. Knockdown of KLF4 in breast cancer cells (MCF-7 and MDA-MB-231) decreased the proportion of stem/progenitor cells as demonstrated by expression of stem cell surface markers such as aldehyde dehydrogenase 1, side population and by
in vitro
mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation
in vitro
and inhibited tumorigenesis in immunocompromised non-obese diabetic/severe combined immunodeficiency mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 has a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell–like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer.</description><subject>631/67/1347</subject><subject>631/67/395</subject><subject>631/67/71</subject><subject>631/80/84/2336</subject><subject>Aldehyde dehydrogenase</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - pathology</subject><subject>Breast Neoplasms - physiopathology</subject><subject>Cancer cells</subject><subject>Cell adhesion & migration</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell physiology</subject><subject>Cell surface</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Colonies</subject><subject>Development and progression</subject><subject>Diabetes mellitus</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Gene Knockdown Techniques</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>KLF4 protein</subject><subject>Krueppel-like factor</subject><subject>Kruppel-Like Transcription Factors - genetics</subject><subject>Kruppel-Like Transcription Factors - physiology</subject><subject>Mammary gland</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Molecular and cellular biology</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Metastasis</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Notch protein</subject><subject>Oncogenes</subject><subject>Oncology</subject><subject>original-article</subject><subject>Physiological aspects</subject><subject>Progenitor cells</subject><subject>Proteins</subject><subject>Receptors, Notch - metabolism</subject><subject>Risk factors</subject><subject>Severe combined immunodeficiency</subject><subject>Signal Transduction</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Surface markers</subject><subject>Transcription factors</subject><subject>Tumor cell lines</subject><subject>Tumorigenesis</subject><subject>Tumorigenicity</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9ks1v1DAQxSMEokvhxhlZVIgikcVfSewLUlVRQF2JC5wtrzNeXBJ7aycV_Pc4ZNmliCIfrPH8_Kw3fkXxlOAlwUy8Cd4sKc5VJcm9YkF4U5dVJfn9YoFlhUtJGT0qHqV0hTFuJKYPiyNKKKeyIYvi-2Uct1voys59A2S1GUJEHJ1eri74K-QSinA9uggtsrnRa-cH8NobQMGidQSdBmSmOqI0QI8MdF1C2s_8VKHebaIeXPC_jp2_0SkXj4sHVncJnuz24-LLxbvP5x_K1af3H8_PVqWpGRlKpoXF1lStFZSYlkgptRQVJwyzqmHS1pK0RmLZcFZn6w1oDevKNMyCJIKx4-LtrLsd1z20BvwQdae20fU6_lBBO3W7491XtQk3imEhGkGzwMudQAzXI6RB9S5NxrSHMCYl6ooIkeFMnv6XJDhTvBL1JPr8L_QqjNHnQWQ9LjAhdZOhk7sgWnPCCZ3msKc2ugPlvA3ZhpleVme0qkXNJJ6o5T-ovFronQkerMvnty68ni-YGFKKYPcjI1hNwVM5eGoKnsrBy_izP8e8h38nLQMvdoBORnc25tC4dOCyH0Z5nbly5lJu-Q3Eg-k7HkYz7_UwRjh8rDcTMyE_Aevt9z0</recordid><startdate>20110505</startdate><enddate>20110505</enddate><creator>Yu, F</creator><creator>Li, J</creator><creator>Chen, H</creator><creator>Fu, J</creator><creator>Ray, S</creator><creator>Huang, S</creator><creator>Zheng, H</creator><creator>Ai, W</creator><general>Nature Publishing Group UK</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</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>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110505</creationdate><title>Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion</title><author>Yu, F ; Li, J ; Chen, H ; Fu, J ; Ray, S ; Huang, S ; Zheng, H ; Ai, W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c631t-3a8f0fc5df821cd1999a985413035739f691dc90974364767eaaeb5c73fe91833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>631/67/1347</topic><topic>631/67/395</topic><topic>631/67/71</topic><topic>631/80/84/2336</topic><topic>Aldehyde dehydrogenase</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - pathology</topic><topic>Breast Neoplasms - physiopathology</topic><topic>Cancer cells</topic><topic>Cell adhesion & migration</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell physiology</topic><topic>Cell surface</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Colonies</topic><topic>Development and progression</topic><topic>Diabetes mellitus</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Gene Knockdown Techniques</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>KLF4 protein</topic><topic>Krueppel-like factor</topic><topic>Kruppel-Like Transcription Factors - genetics</topic><topic>Kruppel-Like Transcription Factors - physiology</topic><topic>Mammary gland</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Molecular and cellular biology</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Metastasis</topic><topic>Neoplastic Stem Cells - cytology</topic><topic>Notch protein</topic><topic>Oncogenes</topic><topic>Oncology</topic><topic>original-article</topic><topic>Physiological aspects</topic><topic>Progenitor cells</topic><topic>Proteins</topic><topic>Receptors, Notch - metabolism</topic><topic>Risk factors</topic><topic>Severe combined immunodeficiency</topic><topic>Signal Transduction</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Surface markers</topic><topic>Transcription factors</topic><topic>Tumor cell lines</topic><topic>Tumorigenesis</topic><topic>Tumorigenicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, F</creatorcontrib><creatorcontrib>Li, J</creatorcontrib><creatorcontrib>Chen, H</creatorcontrib><creatorcontrib>Fu, J</creatorcontrib><creatorcontrib>Ray, S</creatorcontrib><creatorcontrib>Huang, S</creatorcontrib><creatorcontrib>Zheng, H</creatorcontrib><creatorcontrib>Ai, W</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>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Proquest Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, F</au><au>Li, J</au><au>Chen, H</au><au>Fu, J</au><au>Ray, S</au><au>Huang, S</au><au>Zheng, H</au><au>Ai, W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2011-05-05</date><risdate>2011</risdate><volume>30</volume><issue>18</issue><spage>2161</spage><epage>2172</epage><pages>2161-2172</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriched populations in mouse primary mammary tumor and breast cancer cell lines. Knockdown of KLF4 in breast cancer cells (MCF-7 and MDA-MB-231) decreased the proportion of stem/progenitor cells as demonstrated by expression of stem cell surface markers such as aldehyde dehydrogenase 1, side population and by
in vitro
mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation
in vitro
and inhibited tumorigenesis in immunocompromised non-obese diabetic/severe combined immunodeficiency mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 has a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell–like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>21242971</pmid><doi>10.1038/onc.2010.591</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67/1347 631/67/395 631/67/71 631/80/84/2336 Aldehyde dehydrogenase Apoptosis Biological and medical sciences Breast cancer Breast Neoplasms - pathology Breast Neoplasms - physiopathology Cancer cells Cell adhesion & migration Cell Biology Cell Line, Tumor Cell migration Cell physiology Cell surface Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Colonies Development and progression Diabetes mellitus Fundamental and applied biological sciences. Psychology Gene expression Gene Knockdown Techniques Gynecology. Andrology. Obstetrics Health aspects Human Genetics Humans Internal Medicine KLF4 protein Krueppel-like factor Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - physiology Mammary gland Mammary gland diseases Medical sciences Medicine Medicine & Public Health Molecular and cellular biology Neoplasm Invasiveness Neoplasm Metastasis Neoplastic Stem Cells - cytology Notch protein Oncogenes Oncology original-article Physiological aspects Progenitor cells Proteins Receptors, Notch - metabolism Risk factors Severe combined immunodeficiency Signal Transduction Stem cell transplantation Stem cells Surface markers Transcription factors Tumor cell lines Tumorigenesis Tumorigenicity Tumors |
| title | Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion |
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