1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation.

Background: The triple-negative subgroup of breast cancer includes a cluster of tumors exhibiting low E-cadherin expression (metaplastic carcinomas). In several cancer models, lalpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) induces differentiation by increasing E-cadherin expression. The Vitamin D receptor (VDR) was evaluated as a possible therapeutic target for metaplastic carcinomas and 1 alpha,25(OH)(2)D-3 effects as a differentiating agent in triple-negative breast cancer cells were assessed. Materials and Methods: Metaplastic carcinomas were assessed for VDR expression by immunohistochemistry; differences in E-cadherin expression in triple-negative breast cancer cells were evaluated by real-time PCR, western blotting and Cadherin 1 (CDH1) methylation status. Results: Most of the metaplastic carcinomas were positive for VDR expression. Furthermore, 1 alpha,25(OH)(2)D-3 promoted differentiation of MDA-MB-231 cells by inducing de novo E-cadherin expression, an effect that was time- and dose-dependent. Also, E-cadherin expression was due to promoter demethylation. Conclusion: Metaplastic carcinomas may respond to 1 alpha,25(OH)(2)D-3, since they express VDR and 1 alpha,25(OH)(2)D-3 induces de novo E-cadherin expression in breast cancer cells by promoter demethylation.