The DNA methyl-transferase protein DNMT1 enhances tumor-promoting properties of breast stromal fibroblasts

Abstract
The activation of breast stromal fibroblasts plays a vital role in tumor growth and metastasis. Understanding the molecular mechanisms behind this activation is essential for identifying the key molecules and processes that maintain it. In this study, we highlight the significance of the DNA methyltransferase protein DNMT1 in both activating breast stromal fibroblasts and sustaining their active state. We first observed that DNMT1 is upregulated in most cancer-associated fibroblasts compared to adjacent normal fibroblasts, a change attributed to the HuR-dependent stabilization of DNMT1 mRNA. Additionally, when DNMT1 was expressed in primary normal breast fibroblasts, it induced pro-carcinogenic effects in vitro and in orthotopic tumor xenografts. Conversely, specific knockdown of DNMT1 reverted breast myofibroblasts to a normal state and inhibited their cancer-promoting capabilities. These effects were maintained through the disruption of the IL-6/STAT3/NF-κB epigenetic feedback loop related to cancer and inflammation. We also found that the DNMT1-mediated activation of breast fibroblasts involves the upregulation of the RNA-binding protein AUF1, which is part of this loop. Overall, our findings underscore the critical role of DNMT1 in the GSK3685032 sustained activation of breast stromal fibroblasts associated with breast cancer.