Sensitization to tamoxifen by tanshinone IIA in tamoxifen-resistant breast cancer cells in vitro

The treatment success of tamoxifen is mainly dependent on the expression of the estrogen receptor (ER) in the breast carcinoma. However, a large percent of responding patients ultimately develop tamoxifen resistance. Given that increasing evidence has shown that miRNAs are involved in modulating tamoxifen resistance and Tanshinone IIA (TSA) exhibits great anti-cancer effects on both ER-positive and -negative breast cancer cells, the present study examined the effects of TSA on tamoxifen resistance. To this end, we derived a tamoxifen-resistant breast cancer cell line (i.e., MCF-7-TamR) using MCF-7 cells. We evaluated the effects of tamoxifen and TSA treatment on the proliferation, clonogenic potential, and apoptosis of MCF-7 and MCF-7-TamR cells, and explored the expression of miRNAs after TSA treatment in MCF-7 and MCF-7-TamR cells. Our results showed that 0.1, 0.5, or 1 mu M, but not 5 or 10 mu M, tamoxifen failed to alter cell proliferation in tamoxifen-resistant MCF-7-TamR cells. However, a low dose of TSA (0.05 mu M) treatment, which alone failed to alter the proliferation in either MCF-7 or MCF-7-TamR cells, was able to attenuate cell proliferation and clonogenic potential, and increase apoptosis in tamoxifen-resistant MCF-7-TamR cells when co-treated with 1 mu M of tamoxifen. Furthermore, 0.05 mu M of TSA treatment alone enhanced the expression of miRNA-22 in MCF-7 or MCF-7-TamR cells, which is correlated with attenuated expression of c-Myc. Taken together, our results suggested that low dose of TSA promotes the sensitivity to tamoxifen in tamoxifen-resistant cells in vitro likely involving miRNA-22 and c-Myc mediated signaling pathways.