Genistein Affects HER2 Protein Concentration, Activation and Promoter Regulation via Estrogen Receptor-and non-Estrogen Receptor-Mediated Mechanisms

dc.contributor.author Sakla, Mary
dc.contributor.author MacDonald, Ruth
dc.contributor.author Ansell, Pete
dc.contributor.author Shenouda, Nader
dc.contributor.author Lubahn, Dennis
dc.contributor.author MacDonald, Ruth
dc.contributor.department Food Science and Human Nutrition
dc.date 2018-02-15T03:18:47.000
dc.date.accessioned 2020-06-30T03:59:49Z
dc.date.available 2020-06-30T03:59:49Z
dc.date.copyright Mon Jan 01 00:00:00 UTC 2007
dc.date.embargo 2014-01-11
dc.date.issued 2007-10-02
dc.description.abstract <p>The <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> proto-oncogene, a member of the epidermal growth factor receptor family, is overexpressed in 20–30% of breast cancers. <a href="http://link.springer.com/search?dc.title=Genistein&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">Genistein</a>, the main soy isoflavone, interacts with estrogen receptors (ER) and it is also a potent tyrosine kinase inhibitor. Previously, our laboratory found that genistein delayed mammary tumor onset in transgenic mice that overexpress <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> gene. Our goal was to define the mechanism through which genistein affects mammary tumorigenesis in<em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> overexpressing mice. We hypothesized that genistein inhibits <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> activation and expression through ER-dependent and ER-independent mechanisms. <a href="http://link.springer.com/search?dc.title=Genistein&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">Genistein</a> inhibited total <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> protein expression and tyrosine phosphorylation in BT-474, an ERα (−) and ERβ (+) human breast cancer cell line, however, E2 had no effect. Taken together, these data suggest that genistein has an ER-independent inhibitory effect, presumably, through tyrosine kinase inhibition activity. <a href="http://link.springer.com/search?dc.title=Genistein&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">Genistein</a> at 1.0 μM mimicked E2 and down-regulated <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> protein phosphorylation when BT-474 was co-transfected with ERα, but not ERβ. Although E2 and overexpression of <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> can promote mammary tumorigenesis, an inverse relationship between ER expression and <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> overexpression has been found in human breast cancer. We cloned a 500-bp promoter region upstream of the<em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> transcription initiation site. Co-transfection with ERα, but not with ERβ, down-regulated <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em>promoter reporter in BT-474. At concentrations ≥1 μM, genistein inhibited <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> promoter reporter in the absence of ERα. In conclusion, genistein at ≥1 μM inhibited <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> protein expression, phosphorylation, and promoter activity through an ER-independent mechanism. In the presence of ERα, genistein mimicked E2 and inhibited <em><a href="http://link.springer.com/search?dc.title=HER2&facet-content-type=ReferenceWorkEntry&sortOrder=relevance">HER2</a></em> protein phosphorylation. These data support genistein’s chemo-prevention and potential chemo-therapeutic roles in breast cancer.</p>
dc.description.comments <p>This is a manuscript of an article from Endocrine 32 (2007): 69. doi: <a href="http://www.dx.doi.org/10.1007/s12020-007-9006-1" target="_blank">10.1007/s12020-007-9006-1</a>. Posted with permission. "The Original Publication is Available at www.springerlink.com"</p>
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dc.identifier archive/lib.dr.iastate.edu/fshn_ag_pubs/78/
dc.identifier.articleid 1075
dc.identifier.contextkey 6267546
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath fshn_ag_pubs/78
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/37591
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/fshn_ag_pubs/78/2007_MacDonaldRS_GenisteinAffectsHER.pdf|||Sat Jan 15 01:53:58 UTC 2022
dc.source.uri 10.1007/s12020-007-9006-1
dc.subject.disciplines Cancer Biology
dc.subject.disciplines Food Science
dc.subject.disciplines Human and Clinical Nutrition
dc.subject.disciplines Women's Health
dc.subject.keywords Genistein
dc.subject.keywords HER2
dc.subject.keywords er
dc.subject.keywords Breast Cancer
dc.title Genistein Affects HER2 Protein Concentration, Activation and Promoter Regulation via Estrogen Receptor-and non-Estrogen Receptor-Mediated Mechanisms
dc.type article
dc.type.genre article
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relation.isAuthorOfPublication bfbd6b6b-8feb-40d3-8ccb-42c0d0b238d7
relation.isOrgUnitOfPublication 4b6428c6-1fda-4a40-b375-456d49d2fb80
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