Tumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem as a unifying molecular mechanism of tamoxifen resistance has remained elusive.
Researchers at UC, Denver and Tulane University examined the influence of microRNAs (miRNAs) on tamoxifen resistance in both breast tumor samples and cell models of tamoxifen resistance. They compared miRNA expression profiles of tamoxifen sensitive and tamoxifen resistant MCF-7 cells and observed significant and dramatic downregulation of miR-342 in the tamoxifen resistant cells. Expression of miR-342 was also reduced in a panel of tamoxifen refractory human breast tumors, underscoring the potential clinical importance of miR-342 downregulation.
Restoring miR-342 expression in the resistant MCF-7 cell lines sensitized these cells to tamoxifen-induced apoptosis with a dramatic reduction in cell growth. Global gene expression analysis of the restored cells by microarray identified direct and indirect targets of miR-342 not limited to those predicted in silica.
These findings suggest that miR-342 regulates tamoxifen response in breast tumor cell lines and the clinical data indicates a trend towards reduced miR-342 expression and tamoxifen resistance. In addition, the results suggest that miR-342 regulates expression of genes involved in tamoxifen mediated tumor cell apoptosis and cell cycle progression. Restoring miR-342 expression may represent a novel therapeutic approach to sensitizing and suppressing the growth of tamoxifen refractory breast tumors.
Cittelly DM, Das PM, Spoelstra NS, Edgerton SM, Richer JK, Thor AD, Jones FE. (2010) Downregulation of miR-342 is Associated with Tamoxifen Resistant Breast Tumors. Mol Cancer [Epub ahead of print]. [article]