Abstract
The activation of breast stromal fibroblasts is a crucial step toward tumor growth and spread. Therefore, it is extremely important to understand the molecular basis of this activation and determine the molecules and the mechanisms responsible for its sustainability. In the present report we have shown that the DNA methyl-transferase protein DNMT1 is critical for the activation of breast stromal fibroblasts as well as the persistence of their active status. Indeed, we have first revealed DNMT1 up-regulation in most cancer-associated fibroblasts relative to their corresponding adjacent normal fibroblasts. This effect resulted from HuR-dependent stabilization of the DNMT1 mRNA. Furthermore, ectopic expression of DNMT1 activated primary normal breast fibroblasts and promoted their pro-carcinogenic effects, both in vitro and in orthotopic tumor xenografts. By contrast, specific DNMT1 knockdown normalized breast myofibroblasts and repressed their cancer-promoting properties. These effects were sustained through inhibition of the IL-6/STAT3/NF-κB epigenetic cancer/inflammation positive feedback loop. Furthermore, we have shown that DNMT1-related activation of breast fibroblasts is mediated through upregulation of the RNA binding protein AUF1, which is also part of the loop. The present data demonstrate the critical function of DNMT1 in breast cancer-related sustained activation of breast stromal fibroblasts.
Highlights
Breast cancer is a major health problem that threatens the lives of millions of women worldwide [1]
DNMT1 level was similar in 2 cancer-associated fibroblasts (CAFs)/TCF pairs 180 and 87, while it was lower in CAF-346 and CAF-69 compared to their paired TCF cells (Figure 1B)
The DNMT1 mRNA was more stable in different CAFs relative to their corresponding TCFs, suggesting the role of cancer cells in slowing-down the DNMT1 mRNA turnover leading to its accumulation in the surrounding fibroblasts
Summary
Breast cancer is a major health problem that threatens the lives of millions of women worldwide [1]. We have recently shown that the sustained active pro-carcinogenic effects of CAFs is mediated through the stimulation of the positive IL-6/ STAT3/NF-κB feedback loop [6]. This loop maintains the epigenetic transformed state of cells for many generations in the absence of the inducing signal. DNMT1 has de novo activity in human cancer cells and plays important roles in maintaining genome stability [12, 13]. The expression of DNMT1 was found to be higher in triple negative breast cancer and lower in luminal A samples [15] These results and others have shown that DNMT1 plays crucial roles in breast carcinogenesis. Since breast stromal fibroblasts are major players in this complex process, we sought to investigate the role of DNMT1 in these mesenchymal cells
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