Importance of Ets1 Proto-Oncogene for Breast Cancer Progression

Abstract

Ets proteins are transcription factors, which share a unique DNA binding domain, the Ets domain. Some members of the Ets family are implicated in tumorigenesis. Ets1, the founder of the Ets family, is predominantly expressed in invasive tumors and able to activate certain genes encoding ECM-degrading proteases. We used RNA-interference in combination with DNA chip analysis to identify Ets1-regulated genes in MDA-MB-231 breast cancer cells. Of the Ets1-responsive proteases, matrix metalloproteases MMP1 and MMP9, but not MMP3 or uPA, showed reduced RNA levels when endogenous Ets1 expression was suppressed. These data suggest that Ets1 regulates only a certain subset of ECM-degrading proteases. How Ets1 is regulated in invasive breast cancer cells is unknown. The observations that protein kinase C inhibitors abrogated Ets1 expression and that protein kinase C was able to increase Ets1-dependent transcription imply that protein kinase C is a potential regulator of Ets1 activity in breast cancer cells.

Zusammenfassung

Ets-Proteine bilden eine Familie von Transkriptionsfaktoren, die sich durch eine spezifische DNA-Bindungsdomäne (Ets-Domäne) auszeichnen. Ets1, das erste Mitglied dieser Familie, ist präferenziell in invasiven Tumoren exprimiert und fähig, bestimmte Proteasengene zu aktivieren. RNA-Interferenz in Kombination mit DNA-Chip-Analyse wurde eingesetzt, um Ets1-regulierte Gene in MDA-MB-231-Brustkrebszellen zu identifizieren. Infolge der Unterdrückung der endogenen Ets1-Synthese wurde die Expression der Matrixmetalloproteasen MMP1 und MMP9, nicht aber die von MMP3 oder uPA, reduziert. Diese Daten zeigen, dass nur bestimmte Proteasen von Ets1 reguliert werden. Um die Regulation von Ets1 in Brustkrebszellen zu studieren, wurde eine Reihe von Inhibitoren eingesetzt. Mit Proteinkinase C-Hemmer ließ sich die Ets1-Expression komplett unterdrücken. Außerdem konnte die Ets1-abhängige Transkription durch Proteinkinase C verstärkt werden. Dies weist auf eine potentielle Bedeutung der Proteinkinase C als ein Regulator von Ets1 in invasiven Brustkrebszellen hin.

Ets proteins - PKC - proteases

Ets-Proteine - PKC - Proteasen

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