The role of transcription factor Snail1 in the regulation of hormonal sensitivity of in vitro cultured breast cancer cells

: The loss of hormonal dependency in breast tumor cells is often accompanied by epithelial-mesenchymal transition (EMT) features and an increase in cell metastasizing and invasiveness. Here we studied the role of transcription factors Snail1--the central mediator of EMT, in the progression of hormonal resistance of breast cancer cells. The experiments were performed on the estrogen receptor(ER)-positive estrogen-dependent MCF-7 breast cancer cells, ER-positive estrogen-resistant MCF-7/LS subline generated through long-term cultivation of the parental cells in steroid-free medium, and ER-negative estrogen-resistant HBL-100 breast cancer cells. We found that decrease in the estrogen dependency of breast cancer cells is accompanied by an increase in Snail1 expression and activity, and demonstrated the Snail1 involvement in the negative regulation of ER. NF-kappaB was found to serve as a positive regulator of Snail1 in breast cancer cells, and simultaneous inhibition of NF-kappaB and Snail1 by RNA interference resulted in marked increase of cell response to antiestrogen tamoxifen. In general, the results obtained demonstrate that direct inhibition of NF-kappaB and Snail1 partially restores the estrogen receptor machinery, and show that Snail1 and NF-kappaB may serve as an important targets in the treatment of breast cancer.