Journal
CANCER GENE THERAPY
Volume 21, Issue 7, Pages 290-296Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cgt.2014.29
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Funding
- National Natural Science Foundation of China [81170257]
- Zhejiang Provincial Natural Science Foundation [Y2110513]
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Aberrantly expressed microRNAs (miRNAs) are involved in breast tumorigenesis. It is still unclear if and how miRNAs-221/222 are implicated in breast cancer and the resistance to estrogen receptor modulator tamoxifen. We investigated the roles and mechanisms of miR-221/222 in breast cancer cells, particularly in modulating response to tamoxifen therapy. MCF-7 and MDA-MB231 breast cancer cells were transfected with antisense oligonucleotides AS-miR-221 and AS-miR-222 and their expression of miR-221 and miR-222 was assessed. The correlation of miR-221/222 with tissue inhibitor of metalloproteinase-3 (TIMP3) expression was investigated by fluorescence quantitative PCR and western blotting analysis. The therapeutic sensitivity of these cells, transfected and untransfected, to tamoxifen was determined. Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P< 0.05-0.01). Downregulation of miR-221/222 significantly increased the expression of TIMP3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tannoxifen (P< 0.05-0.01). We have demonstrated for the first time that suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tannoxifen. This effect is mediated through upregulation of TIMP3. These findings suggest that upregulation of TIMP3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer.
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