The phenomenon of the cross-resistance of breast cancer to target and hormonal drugs: the role of epigenetic reconstruction

Earlier we have shown that prolonged treatment of MCF-7 breast cancer cells with mTOR inhibitors, rapamycin or metformin, results in the development of the resistant clones that characterized with constitutive activation of growth-related pathways. Because the activation of bypass growth signaling is among the key features of the acquired hormonal resistance we proposed the existence of the common mechanisms respondent for formation of the cell resistance to both mTOR-targeting and hormonal agents.

The experiments were performed on the MCF-7 breast cancer cells and rapamycin- and tamoxifen-resistant sublines developed under prolonged treatment of the parent cells with rapamycin or tamoxifen, respectively. The comparative analysis of the cell sensitivity to indicated drugs revealed the high level of cross-resistance to rapamycin and tamoxifen in the both sublines. Similar to rapamycin-resistant subline, the tamoxifen-resistant cells were characterized with the constitutive activation of PI3K/Akt signaling along with the suppression of estrogen receptor activity. Analysis of the epigenetic machinery revealed the common features in the expression of DNA methyltransferases: significant suppression of the DNMT3A expression in the both resistant sublines, which correlated with a global change in DNA methylation detected by demethylation of LINE-1 elements. Knockdown of the DNMT3A by siRNA resulted in the partial resistance of the MCF-7 cells to tamoxifen and rapamycin. Totally, the results obtained highlight the possible mechanism of the tumor cell resistance to targeting/hormonal drugs based on the rearrangement of DNA methylation profile and changes in the epigenetic regulation of cell signaling.