Abstract
Estrogen receptor-positive breast cancers are treated with tamoxifen, a drug that competitively inhibits the binding of estrogen to its receptor. Resistance to tamoxifen is a major hurdle in effective management of target breast cancer patient population. A number of dynamic changes within the tumor microenvironment, including the phenomenon of epithelial to mesenchymal transition (EMT), determine the response to endocrine therapy. EMT is marked by silencing or suppression of epithelial marker, E-Cadherin and we found significantly down-regulated E-Cadherin, among other epithelial markers, and a significantly up-regulated mesenchymal marker, Twist, among other mesenchymal markers, in a model system that comprised of tamoxifen sensitive MCF-7 cells and their tamoxifen-resistant counterparts, MCF-7-TAM, developed by chronic and escalating exposure of parental cells to tamoxifen. Further, E-cadherin, but not Twist, was differentially expressed in MCF-7-TAM cells because of differential methylation. Treatment with demethylating agent 5-azacytidine increased the expression of E-cadherin thus verifying a role of methylation in its silencing and, moreover, 5-azacytidine treatment also re-sensitized MCF-7-TAM cells to tamoxifen, as evaluated by assays for viability, apoptosis and migration potential. The 5-azacytidine effects were similar to effects of E-cadherin overexpression in MCF-7-TAM cells. This work describes novel mechanism of E-cadherin downregulation in tamoxifen resistant breast cancer cells. Further studies are needed to exploit this information for betterment of breast cancer therapy.
Highlights
Epithelial to mesenchymal transition (EMT) has been target of research in the fight against drug resistance in breast cancer for several years[9,10,11,12]
There still was a dose-dependent decrease in viability of parental MCF-7 and tamoxifen resistant MCF-7-TAM cells, but the MCF-7-TAM cells were significantly (p < 0.01) more resistant than the parental cells
We found through dose-and time-dependent analyses that MCF-7-TAM cells were considerably more resistant to tamoxifen than the parental cells, and were an excellent model to study the mechanism of induced tamoxifen resistance
Summary
Epithelial to mesenchymal transition (EMT) has been target of research in the fight against drug resistance in breast cancer for several years[9,10,11,12]. Even the phenomenon of resistance to tamoxifen in estrogen receptor positive breast cancer cells is believed to involve EMT as one of the mechanism[13,14,15,16,17]. EMT fundamentally involves a transition from more organized and robust epithelial to a considerably more motile mesenchymal phenotype. Even though E-cadherin is often evaluated with respect to its relative expression in cells www.nature.com/scientificreports/. Www.nature.com/scientificreports undergoing EMT, the mechanistic details of down-regulation of E-cadherin, its epigenetic regulation, if any, and in the context of resistance against tamoxifen are totally unknown
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