Targeting of Runx2 by miR-135 and miR-203 Impairs Progression of Breast Cancer and Metastatic Bone Disease

Abstract

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 microRNAs (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 IL-11, MMP-13, and PTHrP. Additionally, 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 therapeutic approach to prevent metastatic bone disease by this route.

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

“…Given that recent literature has described an inhibitory effect of miR-203 on RUNX2 expression in breast cancer cells (94) and that dn-RUNX2 determines bone loss in estrogen deficiency, (95) future research should elucidate whether these two miRNAs are implicated in pathways which might be promising targets for fracture in general.…”

RUNX2 Plays An Oncogenic Role in Esophageal Carcinoma by Activating the PI3K/AKT and ERK Signaling Pathways

“…For instance, RUNX2 is abnormally expressed in highly metastatic prostate cancer cells and may function as a key regulator in prostate cancer metastatic bone disease [12,13]. Targeting of RUNX2 is found to impair the progression of breast cancer to metastatic bone disease [14] and repress cell growth and metastasis of lung cancer cells [15]. In addition, RUNX2 can promote the metastasis of human gastric cancer through up-regulation of the chemokine receptor CXCR4 [16].…”

Direct interaction between miR-203 and ZEB2 suppresses epithelial–mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance

“…miR-203 has been previously implicated in the pathogenesis of many tumor types including colorectal cancer [1], gastric cancer [2], breast cancer [3], melanoma [4], and liver cancer [5]. In lung cancer, miR-203 functions as a tumor suppressor which represses cell proliferation and metastasis [6] by targeting Bmi1 and PKCα [7,8].…”