Role of miRNAs in Breast Cancer-induced Bone Disease

Abstract

Bone is the most common site of breast cancer recurrence. Despite the increasing knowledge about the metastatic process and treatment advances, the disease still remains incurable once the cancer cells actively proliferate in bone. Complex interactions between cancer cells and cells of the bone microenvironment (BME) regulate the initiation and progression of metastatic tumor growth in bone. In particular, breast cancer cells shift the otherwise tightly balanced bone remodeling towards increased bone resorption by osteoclasts. Cellular interactions in the metastatic BME are to a large extent regulated by secreted molecules. These include various cytokines as well as microRNAs (miRNAs), small non-coding RNAs that post transcriptionally regulate protein abundance in several cell types. Through this mechanism, miRNAs modulate physiological and pathological processes including bone remodeling, tumorigenesis and metastasis. Consequently, miRNAs have been identified as important regulators of cellular communication in the metastatic BME. Disruption of the crosstalk between cancer cells and the BME has emerged as a promising therapeutic target to prevent the establishment and progression of breast cancer bone metastasis. In this context, miRNA mimics or antagonists present innovative therapeutic approaches of high potential for interfering with pathological bone – cancer cell interactions. This review will discuss the role of miRNAs in the tumor-BME crosstalk in vivo and will emphasize how this could be targeted by miRNAs to improve therapeutic outcome for patients with breast cancer bone metastases.

Zusammenfassung

Beginnt ein Brustkrebs zu metastasieren, streuen die Tumorzellen häufig in die Knochen. Trotz zunehmender Kenntnisse über den Metastasierungsprozess und fortschreitender Therapiemöglichkeiten bleibt die Krankheit dennoch unheilbar, sobald Krebszellen im Knochen proliferieren und dort Metastasen ausbilden. Komplexe molekulare und zelluläre Interaktionen zwischen Tumorzellen und Zellen des Knochenmilieus regulieren die Initiierung und das Fortschreiten des Wachstums der Metastasen im Knochen. Dabei verlagern Brustkrebszellen das eng regulierte Gleichgewicht des Knochenauf- und -Abbaus zu einem erhöhten Knochenabbau durch Osteoklasten. Zelluläre Interaktionen in einem durch Metastasen gestörten Knochenmilieu werden durch verschiedene Moleküle reguliert; dazu zählen u. a. Zytokine sowie MicroRNAs (miRNAs). MiRNAs sind kurze, nicht-kodierende RNA Sequenzen, die an spezifische Zielsequenzen kodierender mRNAs binden und diese einer Degradierung zuführen. Ferner können miRNAs die Proteinbiosynthese von Ziel-mRNAs unterbinden und über diese beiden Mechanismen die Konzentration der entsprechenden Proteine reduzieren. Auf der Grundlage dieser Mechanismen können miRNAs neben physiologischen Mechanismen, auch krankhafte Prozesse einschließlich der Tumorentstehung, der Metastasierung und des durch Metastasen gestörten Knochenumbaus beeinflussen. Diese Erkenntnisse etablieren miRNAs als wichtige Regulatoren der zellulären Kommunikation des metastatischen Knochenmilieus. Folglich hat sich die Unterbrechung dieses Mechanismus und damit des zellulären Austauschs zwischen Tumorzellen und dem umgebenden Knochenmilieu auch als möglicher Therapieansatz herausgestellt. Durch diesen Ansatz ließe sich die Initiierung und das Voranschreiten von Brustkrebsmetastasen im Knochen reduzieren oder die Zerstörung des Knochens behandeln. Deshalb ist die Behandlung von Krebspatienten mit miRNA Mimetika oder Antagonisten ein vielversprechender therapeutischer Ansatz für eine etwaige zukünftige Verbesserung der Krebstherapie. RNA-Interferenz als Behandlungsprinzip ist bereits in der Klinik (s. Hesse et al. in dieser Ausgabe der Osteologie), Delivery-Methoden sind auch im Rahmen moderner Impfstrategien bereits erprobt. Insofern ist die Technologie verfügbar und nach fundierten präklinischen Studien könnte der Weg in die Translation sehr schnell beschritten werden. Um diese neuartigen Entwicklungen darzustellen, diskutiert dieser Review Artikel die Bedeutung von miRNAs im Tumor-Knochenmilieu in vivo und wie diese Interaktionen durch die Verwendung von miRNAs modifiziert werden können. Ferner wird aufgezeigt, wie diese pharmakologischen Interventionen den Behandlungserfolg von Patienten mit Brustkrebsmetastasen im Knochen verbessern könnten.

Key words

bone metastases - breast cancer - miRNA - bone microenvironment

Schlüsselwörter

Knochenmetastasen - Brustkrebs - miRNA - Knochenmilieu

Publication History

Received: 11 May 2021

Accepted: 26 May 2021

Article published online:
17 September 2021

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