Abstract
Resistance to tamoxifen is a major clinical challenge. Research in recent years has identified epigenetic changes as mediated by dysregulated miRNAs that can possibly play a role in resistance to tamoxifen in breast cancer patients expressing estrogen receptor (ER). We report here elevated levels of EMT markers (vimentin and ZEB1/2) and reduced levels of EMT-regulating miR-200 (miR-200b and miR-200c) in ER-positive breast cancer cells, MCF-7, that were resistant to tamoxifen, in contrast with the naïve parental MCF-7 cells that were sensitive to tamoxifen. Further, we established regulation of c-MYB by miR-200 in our experimental model. C-MYB was up-regulated in tamoxifen resistant cells and its silencing significantly decreased resistance to tamoxifen and the EMT markers. Forced over-expression of miR-200b/c reduced c-MYB whereas reduced expression of miR-200b/c resulted in increased c-MYB We further confirmed the results in other ER-positive breast cancer cells T47D cells where forced over-expression of c-MYB resulted in induction of EMT and significantly increased resistance to tamoxifen. Thus, we identify a novel mechanism of tamoxifen resistance in breast tumor microenvironment that involves miR-200-MYB signaling.
Highlights
Resistance to tamoxifen is a major clinical challenge
We could verify that EMT is induced in our model of tamoxifen resistance
We evaluated the IC-50 values of tamoxifen in resistant cells vs. the parental ones and performed a dose-escalation experiment wherein cells were exposed to increasing concentrations of tamoxifen for different durations of time, and IC-50 of tamoxifen was calculated for the normal vs resistant cells
Summary
Resistance to tamoxifen is a major clinical challenge. Research in recent years has identified epigenetic changes as mediated by dysregulated miRNAs that can possibly play a role in resistance to tamoxifen in breast cancer patients expressing estrogen receptor (ER). A number of mechanisms have been proposed and explored for the basis of acquired tamoxifen resistance of ER-positive breast cancer[6], but the clinical problem continues to exist. In recent years, non-coding RNAs, a class to which miRNAs belong, have been linked with the phenomenon of tamoxifen resistance in breast cancer[12,13]. With this background information, we carefully planned our present study the role of EMT and miR-200s in acquired tamoxifen resistance of ER-positive breast cancer cells. We designed our study to elucidate a novel target of miR-200s, the oncogenic c-MYB, that is mechanistically involved in induction of EMT and resulting tamoxifen resistance
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