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

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>