Overexpression of RUNX2 promotes breast cancer multi-organ metastasis through stabilizing c-Myc

Distant metastasis is the leading cause of mortality in breast cancer patients and remains a significant challenge in clinical practice. Although breast cancer metastasis exhibits organotropism, widespread dissemination and synchronous multi-organ metastasis frequently occur in advanced stages, or the early stages of patients suffering from aggressive tumors, even in patients with an undetectable primary tumor. However, the underlying mechanism is still far from being fully understood. Runt-related transcription factor 2 (RUNX2), a master osteogenic transcription factor, is commonly considered a driver of bone-specific metastasis in breast cancer. Surprisingly, we found here that overexpression of RUNX2 drives synchronous multi-organ metastases rather than bone-preferred metastasis in multiple mouse models of breast cancer, regardless of subtype. Mechanistically, RUNX2 physically interacts with c-Myc oncoprotein to prevent FBXW7-mediated ubiquitination and degradation of c-Myc and coordinately activates the transcription and expression of c-Myc target genes, which elicit early progression and spontaneous dissemination from primary tumor mass, rapid engraftment, and unrestrained outgrowth of cancer cells in distant organs. Thus, our findings uncover a novel mechanism of multi-organ metastasis and highlight RUNX2‒c-Myc regulatory axis as a prognostic indicator and a therapeutic target for predicting and managing multi-organ metastatic breast cancer.