| pubmed-article:20453888 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:20453888 | lifeskim:mentions | umls-concept:C0006142 | lld:lifeskim |
| pubmed-article:20453888 | lifeskim:mentions | umls-concept:C0111429 | lld:lifeskim |
| pubmed-article:20453888 | lifeskim:mentions | umls-concept:C1704675 | lld:lifeskim |
| pubmed-article:20453888 | lifeskim:mentions | umls-concept:C1704824 | lld:lifeskim |
| pubmed-article:20453888 | lifeskim:mentions | umls-concept:C0679622 | lld:lifeskim |
| pubmed-article:20453888 | lifeskim:mentions | umls-concept:C0205314 | lld:lifeskim |
| pubmed-article:20453888 | pubmed:issue | 27 | lld:pubmed |
| pubmed-article:20453888 | pubmed:dateCreated | 2010-7-8 | lld:pubmed |
| pubmed-article:20453888 | pubmed:abstractText | 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. | lld:pubmed |
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| pubmed-article:20453888 | pubmed:language | eng | lld:pubmed |
| pubmed-article:20453888 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:20453888 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:20453888 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:20453888 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:20453888 | pubmed:month | Jul | lld:pubmed |
| pubmed-article:20453888 | pubmed:issn | 1476-5594 | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:LieII | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:HuntK KKK | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:TuckerS LSL | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:McKenzieTT | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:BiernackaAA | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:MeijerLL | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:KeyomarsiKK | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:ShawM VMV | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:AkliSS | lld:pubmed |
| pubmed-article:20453888 | pubmed:author | pubmed-author:MittendorfE... | lld:pubmed |
| pubmed-article:20453888 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:20453888 | pubmed:day | 8 | lld:pubmed |
| pubmed-article:20453888 | pubmed:volume | 29 | lld:pubmed |
| pubmed-article:20453888 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:20453888 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:20453888 | pubmed:pagination | 3896-907 | lld:pubmed |
| pubmed-article:20453888 | pubmed:dateRevised | 2011-11-17 | lld:pubmed |
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