Dynamic TGF-β-driven DACT1 expression regulates Wnt signaling during osteolytic bone metastasis

Abstract

Metastasis, the dissemination of tumor cells to distant parts of the body, accounts for 90 percent of cancer-related fatalities. Among breast and prostate cancer patients, 70 percent of metastatic burden can be attributed to metastasis to the bone. Yet, no reliable markers exist to prognose patients at high risk of developing bone metastasis. To identify bone metastasis-promoting factors, we screened for genes over-expressed at least two-fold in highly bone metastatic derivatives of breast cancer cell lines. Among genes identified, Dishevelled-Binding Antagonist of β-Catenin 1 (DACT1) was the only independent prognostic marker of reduced distant bone metastasis-free survival. While existing literature on DACT1 is conflicting, some research suggests that DACT1 is a suppressor of Wnt signaling, a pathway demonstrated by our lab to be active in metastatic cells adjacent to the bone vasculature. The aim of this study is to characterize DACT1 and DACT1-dependent crosstalk between Tgf-β and Wnt signaling during bone metastasis through in vitro assays and in vivo xenograft experiments. Here, we demonstrate that DACT1 is a TGF-β responsive gene that specifically mediates metastasis to the bone by suppressing Wnt signaling and decreasing transcription of TCF/LEF target genes during the mesenchymal/dormant stage and colonization of the bone endothelial niche. This study is one of the first to characterize DACT1-modulated crosstalk between Tgf-β and Wnt signaling during bone metastatic progression and provides a framework to help identify novel prognostic markers for bone metastatic risk.