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Demethylation of the E‐cadherin promoter driven by hepatocytes allows for cell fate‐determining signals in invasive breast cancer cells

Epithelial‐cadherin's (E‐cadherin) transcriptional silencing in most advanced tumors, due to promoter methylation, enables tumor cells to disseminate from the primary mass. However, E‐cadherin‐positive metastatic carcinoma foci do originate from mainly E‐cadherin‐negative primaries. It is unknown if this is due to dissemination of the minority of E‐cadherin‐positive cells or re‐expression of E‐cadherin during metastasis. Here, we demonstrate that co‐culture of hepatocytes with invasive breast cancer cells lacking E‐cadherin triggers an epigenetic reversion in the breast cancer cells resulting in demethylation of the E‐cadherin promoter and subsequent expression on the protein level. We show a similar time‐course for epigenetic reversion of primary human breast cancer explants co‐cultured with hepatocytes. Further, we show that the E‐cadherin ligation between breast cancer cells and hepatocytes is functional and activates the canonical MAPK pathway and Akt pathway in these cancer cells. Our epigenetic‐reversion hypothesis for E‐cadherin represents not only a paradigm shift in the current thinking that absence of E‐cadherin is a fundamental issue, but would also reveal new strategies to combat the initial stages of metastatic disease in breast cancer patients.