Interaktionen zwischen Östrogenrezeptor- und Rezeptor-Tyrosinkinase-Signaltransduktion: Implikationen für die Therapie des Mammakarzinoms

Zusammenfassung

Das Wachstum von malignen Tumoren der Brustdrüse kann durch Östrogene und Wachstumsfaktoren reguliert werden. Die zelluläre Reaktion auf diese Stimuli wird durch Östrogenrezeptoren und Rezeptor-Tyrosinkinasen vermittelt. Diese beiden Signalwege wurden bis vor kurzer Zeit nur isoliert betrachtet, allerdings häufen sich Hinweise darauf, dass ihre Interaktion nicht die Ausnahme, sondern ein Prinzip ihrer Wirkung ist. Ein Beispiel für die mögliche klinische Bedeutung dieser Wechselwirkung ist der Einfluss einer HER-2/neu-Überexpression auf die Wirkung des Antiöstrogens Tamoxifen bei der Behandlung von Patientinnen mit Mammakarzinom. Umgekehrt gibt es Hinweise darauf, dass die „nichtgenomischen“ Effekte von Östradiol die Wirksamkeit von antitumoralen Substanzen hemmen können, die gegen die Rezeptor-Tyrosinkinase-Signaltransduktion gerichtet sind. In dieser Übersicht werden neue Erkenntnisse über die molekularen Mechanismen der Interaktion zwischen zellulärer Östradiolantwort und Wachstumsfaktor-Signaltransduktion ebenso dargestellt wie deren Bedeutung für die Wirkung antitumoraler Substanzen, die in der Therapie des Mammakarzinoms eingesetzt werden.

Abstract

Growth of breast cancer cells is regulated by estrogens and growth factors. Cellular response to these stimuli is mediated by estrogen receptors and receptor tyrosine kinases. Originally both pathways were considered as independent signaling mechanisms. Now there is evidence for a broad cross-talk between these signal transduction pathways. The relationship between overexpression of HER-2/neu receptor tyrosine kinase and tamoxifen resistance is a possible example for the clinical relevance of this signaling cross-talk. Additionally, nongenomic effects of estrogens are able to interfere with the action of antitumoral substances directed against dysregulated receptor tyrosine kinases by activation of kinases downstream the receptor. Novel insights into the molecular mechanisms underlying the cross-talk between both signaling mechanisms and their impact on the efficacy of antitumoral substances directed against these pathways are reviewed.

Schlüsselwörter

Östrogene - Östrogenrezeptoren - Wachstumsfaktoren - Rezeptor-Tyrosinkinasen - Antiöstrogene

Key words

Estrogens - estrogen receptor - growth factor - receptor tyrosine kinases - antiestrogens

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