E-Cadherin as a Chemotherapy Resistance Mechanism on Metastatic Breast Cancer. Annual Summary Report December 15, 2009-December 14, 2010

摘要

Metastasis contributes significantly to the mortality of breast cancer. The loss of E-cadherin expression is a critical event in the initiation of metastasis. However, these studies focus on the role of E-cadherin in dissemination but not colonization, or survival in a new organ environment, such as the liver, a main site of breast cancer metastasis. We hypothesize that signals from the liver cause breast cancer cells to undergo a mesenchymal to epithelial reverting transition (MErT) through the re-expression of E-cadherin, which consequently confers a survival advantage. Co-culture of E-cadherin- negative MDA-MB-231 breast cancer cells with hepatocytes results in the re- expression of E-cadherin as determined by immunblot, flow cytometry, and immunofluorescence. To test whether E-cadherin expression protects breast cancer cells from chemotherapy-induced cell death, an E-cadherin knock-in and knock-out was generated. When cell death was induced by staurosporine, camptothecin, doxorubicin, or taxol, E-cadherin-positive cells were more resistant to cell death. Furthermore, MDAMB- 231 that have re-expressed E- cadherin following hepatocyte coculture are more chemoresistant compared to MDA- MB-231 cells cultured in the absence of hepatocytes. These results reveal that breast cancer cells cultured in the liver microenvironment undergo molecular changes that confer chemoresistance and may help to elucidate why chemotherapy commonly fails to treat metastatic breast cancer.