Activated fibroblasts have an important role in tumorigenesis and metastasis in breast cancer. However, the molecular mechanisms of their pro-carcinogenic behaviour are not well understood. Here, patient samples and human breast cancer cells were used to investigate the mechanisms of fibroblast activation and the potential of CHEK2 as an anti-tumor suppressor. The results showed that CHEK2 is down-regulated in cancer-associated fibroblasts. Additionally, knockdown of CHEK2 induced the secretion of SDF-1 and IL-6 and transdifferentiation to myofibroblasts, which promoted proliferation of epithelial cells and increased metastatic capabilities of breast cancer cells through SDF-1/IL-6 paracrine signalling. Finally, the cancer-promoting behaviour of cancer activated fibroblasts could be reverted through forced overexpression of CHEK2. Overall the researchers demonstrate the non-cell-autonomous tumor suppression activity of CHEK2 and elucidate its important role in the regulatory interaction between breast tumors and their stromal fibroblasts.
CHEK2 represses breast stromal fibroblasts and their paracrine tumor-promoting effects through suppressing SDF-1 and IL-6
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