A novel interaction between HER2/neu and cyclin E in breast cancer
HER2/neu (HER2) and cyclin E are important prognostic indicators in breast cancer. As both are involved in cell cycle regulation we analyzed whether there was a direct interaction between the two. HER2 and cyclin E expression levels were determined in 395 breast cancer patients. Patients with HER2-o...
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| Veröffentlicht in: | Oncogene 2010-07, Vol.29 (27), p.3896-3907 |
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| creator | Mittendorf, E A Liu, Y Tucker, S L McKenzie, T Qiao, N Akli, S Biernacka, A Liu, Y Meijer, L Keyomarsi, K Hunt, K K |
| description | HER2/neu (HER2) and cyclin E are important prognostic indicators in breast cancer. As both are involved in cell cycle regulation we analyzed whether there was a direct interaction between the two. HER2 and cyclin E expression levels were determined in 395 breast cancer patients. Patients with HER2-overexpression and high levels of cyclin E had decreased 5-year disease-specific survival compared with low levels of cyclin E (14% versus 89%,
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| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2900397</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A231506353</galeid><sourcerecordid>A231506353</sourcerecordid><originalsourceid>FETCH-LOGICAL-c671t-ac317a567d0fe2c1c012a8e997b27169a3a1d460df7085620a53b6e342e797473</originalsourceid><addsrcrecordid>eNqFktFrFDEQxoMo9jx981kWRXxxr5Nkk2xeCmc5rVAQRJ9DLjt7puwlNdmr9L83652tlYrkISTzm2_4ho-Q5xQWFHh7HINbMJhegj4gM9ooWQuhm4dkBlpArRlnR-RJzhcAoDSwx-SIQSN427Yz8m5ZhXiFQ-XDiMm60cdQrXH8gRiqs9VndhxwV9nQVe7aDT5Uq0JW64Q2j5WzwWF6Sh71dsj47HDPydf3qy-nZ_X5pw8fT5fntZOKjrV1nCorpOqgR-aoA8psi1qrNVNUasst7RoJXa-gFZKBFXwtkTcMlVaN4nNyste93K232DkMY7KDuUx-a9O1idabu5Xgv5lNvDJMA3A9Cbw5CKT4fYd5NFufHQ6DDRh32ahGKMZ0y_9Pci4FKK4L-fIv8iLuUih7MBI446ptJrlX_4KYbGgDXP7yd6A2dkDjQx-LCzcNNkvGqQDJxaS1uIcqp8OtdzFg78v_nYa3-waXYs4J-5uNUTBTgkxJkJkSZEqCCv7izy3fwL8jU4DXB8BmZ4c-lRD4fMtxYBKK6zmp91wupbDBdGv63sE_Aavt1_c</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2641403647</pqid></control><display><type>article</type><title>A novel interaction between HER2/neu and cyclin E in breast cancer</title><source>MEDLINE</source><source>Springer Journals</source><source>Springer Nature - Connect here FIRST to enable access</source><source>EZB Electronic Journals Library</source><creator>Mittendorf, E A ; Liu, Y ; Tucker, S L ; McKenzie, T ; Qiao, N ; Akli, S ; Biernacka, A ; Liu, Y ; Meijer, L ; Keyomarsi, K ; Hunt, K K</creator><creatorcontrib>Mittendorf, E A ; Liu, Y ; Tucker, S L ; McKenzie, T ; Qiao, N ; Akli, S ; Biernacka, A ; Liu, Y ; Meijer, L ; Keyomarsi, K ; Hunt, K K</creatorcontrib><description>HER2/neu (HER2) and cyclin E are important prognostic indicators in breast cancer. As both are involved in cell cycle regulation we analyzed whether there was a direct interaction between the two. HER2 and cyclin E expression levels were determined in 395 breast cancer patients. Patients with HER2-overexpression and high levels of cyclin E had decreased 5-year disease-specific survival compared with low levels of cyclin E (14% versus 89%,
P
<0.0001).
In vitro
studies were performed in which HER2-mediated activity in HER2-overexpressing breast cancer cell lines was downregulated by transfection with HER2 small interfering RNA or treatment with trastuzumab. Cyclin E expression levels were determined by western blot analysis, and functional effects analyzed using kinase assays, MTT assays were used to assess cell viability as a marker of proliferation and fluorescence-activated cell sorting analysis was used to determine cell cycle profiles. Decreased HER2-mediated signaling resulted in decreased expression of cyclin E, particularly the low molecular weight (LMW) isoforms. Decreased HER2 and LMW cyclin E expression had functional consequences, including decreased cyclin E-associated kinase activity and decreased proliferation, because of increased apoptosis and an increased accumulation of cells in the G1 phase.
In vivo
studies performed in a HER2-overexpressing breast cancer xenograft model confirmed the effects of trastuzumab on cyclin E expression. Given the relationship between HER2 and cyclin E,
in vitro
clonogenic assays were performed to assess combination therapy targeting both proteins. Isobologram analysis showed a synergistic interaction between the two agents (trastuzumab targeting HER2 and roscovitine targeting cyclin E). Taken together, these studies show that HER2-mediated signaling effects LMW cyclin E expression, which in turn deregulates the cell cycle. LMW cyclin E has prognostic and predictive roles in HER2-overexpressing breast cancer, warranting further study of its potential as a therapeutic target.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2010.151</identifier><identifier>PMID: 20453888</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/80/304 ; 692/53/2422 ; 692/699/67/1347 ; Animals ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal - therapeutic use ; Antibodies, Monoclonal, Humanized ; Apoptosis ; Biological and medical sciences ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Care and treatment ; Cell Biology ; Cell cycle ; Cell cycle, cell proliferation ; Cell growth ; Cell Line, Tumor ; Cell physiology ; Cell proliferation ; Cell Proliferation - drug effects ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cell viability ; Cyclin E ; Cyclin E - chemistry ; Cyclin E - genetics ; Cyclin E - metabolism ; Cyclins ; Down-Regulation ; ErbB-2 protein ; Flow cytometry ; Fundamental and applied biological sciences. Psychology ; G1 phase ; G1 Phase - drug effects ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Gynecology. Andrology. Obstetrics ; Human Genetics ; Humans ; Internal Medicine ; Isoforms ; Kinases ; Mammary gland diseases ; Medical prognosis ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Mice, Nude ; Molecular and cellular biology ; Molecular Weight ; Oncology ; original-article ; Patients ; Physiological aspects ; Prognosis ; Protein Binding ; Proteins ; Receptor, ErbB-2 - metabolism ; Risk factors ; Roscovitine ; Signal transduction ; Signal Transduction - drug effects ; siRNA ; Survival Rate ; Therapeutic targets ; Transcription, Genetic ; Transfection ; Trastuzumab ; Tumor cell lines ; Tumors ; Xenografts</subject><ispartof>Oncogene, 2010-07, Vol.29 (27), p.3896-3907</ispartof><rights>Macmillan Publishers Limited 2010</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2010 Nature Publishing Group</rights><rights>Macmillan Publishers Limited 2010.</rights><rights>Copyright Nature Publishing Group Jul 8, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c671t-ac317a567d0fe2c1c012a8e997b27169a3a1d460df7085620a53b6e342e797473</citedby><cites>FETCH-LOGICAL-c671t-ac317a567d0fe2c1c012a8e997b27169a3a1d460df7085620a53b6e342e797473</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.2010.151$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2010.151$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23026084$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20453888$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mittendorf, E A</creatorcontrib><creatorcontrib>Liu, Y</creatorcontrib><creatorcontrib>Tucker, S L</creatorcontrib><creatorcontrib>McKenzie, T</creatorcontrib><creatorcontrib>Qiao, N</creatorcontrib><creatorcontrib>Akli, S</creatorcontrib><creatorcontrib>Biernacka, A</creatorcontrib><creatorcontrib>Liu, Y</creatorcontrib><creatorcontrib>Meijer, L</creatorcontrib><creatorcontrib>Keyomarsi, K</creatorcontrib><creatorcontrib>Hunt, K K</creatorcontrib><title>A novel interaction between HER2/neu and cyclin E in breast cancer</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>HER2/neu (HER2) and cyclin E are important prognostic indicators in breast cancer. As both are involved in cell cycle regulation we analyzed whether there was a direct interaction between the two. HER2 and cyclin E expression levels were determined in 395 breast cancer patients. Patients with HER2-overexpression and high levels of cyclin E had decreased 5-year disease-specific survival compared with low levels of cyclin E (14% versus 89%,
P
<0.0001).
In vitro
studies were performed in which HER2-mediated activity in HER2-overexpressing breast cancer cell lines was downregulated by transfection with HER2 small interfering RNA or treatment with trastuzumab. Cyclin E expression levels were determined by western blot analysis, and functional effects analyzed using kinase assays, MTT assays were used to assess cell viability as a marker of proliferation and fluorescence-activated cell sorting analysis was used to determine cell cycle profiles. Decreased HER2-mediated signaling resulted in decreased expression of cyclin E, particularly the low molecular weight (LMW) isoforms. Decreased HER2 and LMW cyclin E expression had functional consequences, including decreased cyclin E-associated kinase activity and decreased proliferation, because of increased apoptosis and an increased accumulation of cells in the G1 phase.
In vivo
studies performed in a HER2-overexpressing breast cancer xenograft model confirmed the effects of trastuzumab on cyclin E expression. Given the relationship between HER2 and cyclin E,
in vitro
clonogenic assays were performed to assess combination therapy targeting both proteins. Isobologram analysis showed a synergistic interaction between the two agents (trastuzumab targeting HER2 and roscovitine targeting cyclin E). Taken together, these studies show that HER2-mediated signaling effects LMW cyclin E expression, which in turn deregulates the cell cycle. LMW cyclin E has prognostic and predictive roles in HER2-overexpressing breast cancer, warranting further study of its potential as a therapeutic target.</description><subject>631/80/304</subject><subject>692/53/2422</subject><subject>692/699/67/1347</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell cycle</subject><subject>Cell cycle, cell proliferation</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell physiology</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cell viability</subject><subject>Cyclin E</subject><subject>Cyclin E - chemistry</subject><subject>Cyclin E - genetics</subject><subject>Cyclin E - metabolism</subject><subject>Cyclins</subject><subject>Down-Regulation</subject><subject>ErbB-2 protein</subject><subject>Flow cytometry</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>G1 phase</subject><subject>G1 Phase - drug effects</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Mammary gland diseases</subject><subject>Medical prognosis</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Molecular and cellular biology</subject><subject>Molecular Weight</subject><subject>Oncology</subject><subject>original-article</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Prognosis</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Risk factors</subject><subject>Roscovitine</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>siRNA</subject><subject>Survival Rate</subject><subject>Therapeutic targets</subject><subject>Transcription, Genetic</subject><subject>Transfection</subject><subject>Trastuzumab</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFktFrFDEQxoMo9jx981kWRXxxr5Nkk2xeCmc5rVAQRJ9DLjt7puwlNdmr9L83652tlYrkISTzm2_4ho-Q5xQWFHh7HINbMJhegj4gM9ooWQuhm4dkBlpArRlnR-RJzhcAoDSwx-SIQSN427Yz8m5ZhXiFQ-XDiMm60cdQrXH8gRiqs9VndhxwV9nQVe7aDT5Uq0JW64Q2j5WzwWF6Sh71dsj47HDPydf3qy-nZ_X5pw8fT5fntZOKjrV1nCorpOqgR-aoA8psi1qrNVNUasst7RoJXa-gFZKBFXwtkTcMlVaN4nNyste93K232DkMY7KDuUx-a9O1idabu5Xgv5lNvDJMA3A9Cbw5CKT4fYd5NFufHQ6DDRh32ahGKMZ0y_9Pci4FKK4L-fIv8iLuUih7MBI446ptJrlX_4KYbGgDXP7yd6A2dkDjQx-LCzcNNkvGqQDJxaS1uIcqp8OtdzFg78v_nYa3-waXYs4J-5uNUTBTgkxJkJkSZEqCCv7izy3fwL8jU4DXB8BmZ4c-lRD4fMtxYBKK6zmp91wupbDBdGv63sE_Aavt1_c</recordid><startdate>20100708</startdate><enddate>20100708</enddate><creator>Mittendorf, E A</creator><creator>Liu, Y</creator><creator>Tucker, S L</creator><creator>McKenzie, T</creator><creator>Qiao, N</creator><creator>Akli, S</creator><creator>Biernacka, A</creator><creator>Liu, Y</creator><creator>Meijer, L</creator><creator>Keyomarsi, K</creator><creator>Hunt, K K</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>20100708</creationdate><title>A novel interaction between HER2/neu and cyclin E in breast cancer</title><author>Mittendorf, E A ; Liu, Y ; Tucker, S L ; McKenzie, T ; Qiao, N ; Akli, S ; Biernacka, A ; Liu, Y ; Meijer, L ; Keyomarsi, K ; Hunt, K K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c671t-ac317a567d0fe2c1c012a8e997b27169a3a1d460df7085620a53b6e342e797473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>631/80/304</topic><topic>692/53/2422</topic><topic>692/699/67/1347</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Antibodies, Monoclonal, Humanized</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Cell cycle</topic><topic>Cell cycle, cell proliferation</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell physiology</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cell viability</topic><topic>Cyclin E</topic><topic>Cyclin E - chemistry</topic><topic>Cyclin E - genetics</topic><topic>Cyclin E - metabolism</topic><topic>Cyclins</topic><topic>Down-Regulation</topic><topic>ErbB-2 protein</topic><topic>Flow cytometry</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>G1 phase</topic><topic>G1 Phase - drug effects</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetic aspects</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Isoforms</topic><topic>Kinases</topic><topic>Mammary gland diseases</topic><topic>Medical prognosis</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Molecular and cellular biology</topic><topic>Molecular Weight</topic><topic>Oncology</topic><topic>original-article</topic><topic>Patients</topic><topic>Physiological aspects</topic><topic>Prognosis</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>Risk factors</topic><topic>Roscovitine</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>siRNA</topic><topic>Survival Rate</topic><topic>Therapeutic targets</topic><topic>Transcription, Genetic</topic><topic>Transfection</topic><topic>Trastuzumab</topic><topic>Tumor cell lines</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mittendorf, E A</creatorcontrib><creatorcontrib>Liu, Y</creatorcontrib><creatorcontrib>Tucker, S L</creatorcontrib><creatorcontrib>McKenzie, T</creatorcontrib><creatorcontrib>Qiao, N</creatorcontrib><creatorcontrib>Akli, S</creatorcontrib><creatorcontrib>Biernacka, A</creatorcontrib><creatorcontrib>Liu, Y</creatorcontrib><creatorcontrib>Meijer, L</creatorcontrib><creatorcontrib>Keyomarsi, K</creatorcontrib><creatorcontrib>Hunt, K K</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 Complete (ProQuest Database)</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 UK/Ireland</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>PML(ProQuest Medical Library)</collection><collection>Research Library (ProQuest Database)</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>Mittendorf, E A</au><au>Liu, Y</au><au>Tucker, S L</au><au>McKenzie, T</au><au>Qiao, N</au><au>Akli, S</au><au>Biernacka, A</au><au>Liu, Y</au><au>Meijer, L</au><au>Keyomarsi, K</au><au>Hunt, K K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel interaction between HER2/neu and cyclin E in breast cancer</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2010-07-08</date><risdate>2010</risdate><volume>29</volume><issue>27</issue><spage>3896</spage><epage>3907</epage><pages>3896-3907</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>HER2/neu (HER2) and cyclin E are important prognostic indicators in breast cancer. As both are involved in cell cycle regulation we analyzed whether there was a direct interaction between the two. HER2 and cyclin E expression levels were determined in 395 breast cancer patients. Patients with HER2-overexpression and high levels of cyclin E had decreased 5-year disease-specific survival compared with low levels of cyclin E (14% versus 89%,
P
<0.0001).
In vitro
studies were performed in which HER2-mediated activity in HER2-overexpressing breast cancer cell lines was downregulated by transfection with HER2 small interfering RNA or treatment with trastuzumab. Cyclin E expression levels were determined by western blot analysis, and functional effects analyzed using kinase assays, MTT assays were used to assess cell viability as a marker of proliferation and fluorescence-activated cell sorting analysis was used to determine cell cycle profiles. Decreased HER2-mediated signaling resulted in decreased expression of cyclin E, particularly the low molecular weight (LMW) isoforms. Decreased HER2 and LMW cyclin E expression had functional consequences, including decreased cyclin E-associated kinase activity and decreased proliferation, because of increased apoptosis and an increased accumulation of cells in the G1 phase.
In vivo
studies performed in a HER2-overexpressing breast cancer xenograft model confirmed the effects of trastuzumab on cyclin E expression. Given the relationship between HER2 and cyclin E,
in vitro
clonogenic assays were performed to assess combination therapy targeting both proteins. Isobologram analysis showed a synergistic interaction between the two agents (trastuzumab targeting HER2 and roscovitine targeting cyclin E). Taken together, these studies show that HER2-mediated signaling effects LMW cyclin E expression, which in turn deregulates the cell cycle. LMW cyclin E has prognostic and predictive roles in HER2-overexpressing breast cancer, warranting further study of its potential as a therapeutic target.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>20453888</pmid><doi>10.1038/onc.2010.151</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 0950-9232 1476-5594 |
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| subjects | 631/80/304 692/53/2422 692/699/67/1347 Animals Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized Apoptosis Biological and medical sciences Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Care and treatment Cell Biology Cell cycle Cell cycle, cell proliferation Cell growth Cell Line, Tumor Cell physiology Cell proliferation Cell Proliferation - drug effects Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cell viability Cyclin E Cyclin E - chemistry Cyclin E - genetics Cyclin E - metabolism Cyclins Down-Regulation ErbB-2 protein Flow cytometry Fundamental and applied biological sciences. Psychology G1 phase G1 Phase - drug effects Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Gynecology. Andrology. Obstetrics Human Genetics Humans Internal Medicine Isoforms Kinases Mammary gland diseases Medical prognosis Medical sciences Medicine Medicine & Public Health Mice Mice, Nude Molecular and cellular biology Molecular Weight Oncology original-article Patients Physiological aspects Prognosis Protein Binding Proteins Receptor, ErbB-2 - metabolism Risk factors Roscovitine Signal transduction Signal Transduction - drug effects siRNA Survival Rate Therapeutic targets Transcription, Genetic Transfection Trastuzumab Tumor cell lines Tumors Xenografts |
| title | A novel interaction between HER2/neu and cyclin E in breast cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T18%3A21%3A11IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20novel%20interaction%20between%20HER2/neu%20and%20cyclin%20E%20in%20breast%20cancer&rft.jtitle=Oncogene&rft.au=Mittendorf,%20E%20A&rft.date=2010-07-08&rft.volume=29&rft.issue=27&rft.spage=3896&rft.epage=3907&rft.pages=3896-3907&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2010.151&rft_dat=%3Cgale_pubme%3EA231506353%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2641403647&rft_id=info:pmid/20453888&rft_galeid=A231506353&rfr_iscdi=true |