Targeting of Runx2 by miR-135 and miR-203 Impairs Progression of Breast Cancer and Metastatic Bone Disease
| Autor: | Janet L. Stein, Hanna Taipaleenmaki, Jozef Zustin, Gary S. Stein, Gillian Browne, Andre J. van Wijnen, Jane B. Lian, Eric Hesse, Jacqueline Akech |
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| Rok vydání: | 2015 |
| Předmět: |
musculoskeletal diseases
Cancer Research Pathology medicine.medical_specialty Bone disease Bone Neoplasms Breast Neoplasms Core Binding Factor Alpha 1 Subunit Mice SCID Biology Article Bone resorption Metastasis Breast cancer stomatognathic system Cell Movement Cell Line Tumor microRNA medicine Animals Humans Cell Proliferation Cell growth medicine.disease Metastatic breast cancer Gene Expression Regulation Neoplastic MicroRNAs Oncology Bone Morphogenetic Proteins Disease Progression Cancer research Female RNA Interference miR-203 Neoplasm Transplantation |
| Zdroj: | Cancer Research. 75:1433-1444 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-14-1026 |
| Popis: | Progression of breast cancer to metastatic bone disease is linked to deregulated expression of the transcription factor Runx2. Therefore, our goal was to evaluate the potential for clinical use of Runx2-targeting miRNAs to reduce tumor growth and bone metastatic burden. Expression analysis of a panel of miRNAs regulating Runx2 revealed a reciprocal relationship between the abundance of Runx2 protein and two miRNAs, miR-135 and miR-203. These miRNAs are highly expressed in normal breast epithelial cells where Runx2 is not detected, and absent in metastatic breast cancer cells and tissue biopsies that express Runx2. Reconstituting metastatic MDA-MB-231-luc cells with miR-135 and miR-203 reduced the abundance of Runx2 and expression of the metastasis-promoting Runx2 target genes IL11, MMP-13, and PTHrP. In addition, tumor cell viability was decreased and migration suppressed in vitro. Orthotopic implantation of MDA-MB-231-luc cells delivered with miR-135 or miR-203, followed by an intratumoral administration of the synthetic miRNAs, reduced the tumor growth and spontaneous metastasis to bone. Furthermore, intratibial injection of these miRNA-delivered cells impaired tumor growth in the bone environment and inhibited bone resorption. Importantly, reconstitution of Runx2 in MDA-MB-231-luc cells delivered with miR-135 and miR-203 reversed the inhibitory effect of the miRNAs on tumor growth and metastasis. Thus, we have identified that aberrant expression of Runx2 in aggressive tumor cells is related to the loss of specific Runx2-targeting miRNAs and that a clinically relevant replacement strategy by delivery of synthetic miRNAs is a candidate for a therapeutic approach to prevent metastatic bone disease by this route. Cancer Res; 75(7); 1433–44. ©2015 AACR. |
| Databáze: | OpenAIRE |
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