Author(s): Christopher R Shepard and Alan Wells
Title: Demethylation of the E-cadherin promoter driven by hepatocytes allows for cell fate-determining signals in invasive breast cancer cells
Summary: 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.
Source: FASEB J. 21: 128.4