Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin Induction of the tumor suppressor miRNA let-7a and suppression of the TGF beta-induced oncomiR miRNA-181a

作者：Oliveras Ferraros Cristina; Cufi Slvia; Vazquez Martin Alejandro; Zenobia Torres Garcia Violeta; Del Barco Sonia; Martin Castillo Begona; Menendez Javier A^*

来源：Cell Cycle, 2011, 10(7): 1144-1151.

DOI：10.4161/cc.10.7.15210

• metformin
• microRNA
• let-7
• TGF beta
• miRNA-181
• miRNA-96
• stem cells

An unexplored molecular scenario that might explain the inhibitory impact of the anti-diabetic drug metformin on the genesis of breast cancer relates to metformin's ability to modulate the expression status of micro (mi)RNAs. We here report the first miRNA expression profiling of human epithelial breast cancer cells cultured in the presence of metformin. We conducted real-time transcription polymerase chain reaction (qRT-PCR) Arrays to quantitatively compare the expression profile of 88 cancer-related miRNA sequences before and after treatment of MCF-7 cells, which were used as well-differentiated, epithelioid cell controls, with graded concentrations of metformin. Metformin-treated MCF-7 cells notably exhibited up to 18-fold increases in miRNA lethal-7a (let-7a) expression compared with untreated control cells. We confirmed that MCF-7 cells undergoing epithelial-to-mesenchymal (EMT) transition in response to the cytokine TGF beta notably upregulated (similar to five-fold) miRNA-181a expression and exhibited better mammosphere-forming capabilities. We then explored the ability of metformin to impede TGF beta-enhanced propensity of breast cancer stem cells to form mammospheres in a miRNA-181a-related manner. Remarkably, TGF beta treatment failed to upregulate miRNA-181a expression in the presence of metformin, which was able to fully abrogate TGF beta-enhanced mammosphere-forming ability. In addition, metformin co-treatment fully prevented TGF beta-induced downregulation of the tumor suppressor miRNA-96 (similar to ten-fold). Metformin's molecular functioning to prevent invasive breast cancer can be explained in terms of its previously unrecognized ability to efficiently upregulate the tumor-suppressive miRNAs let-7a & miRNA-96 and inhibit the oncogenic miRNA-181a, thus epigenetically preserving the differentiated phenotype of mammary epithelium while preventing EMT-related cancer-initiating cell self-renewal.

• 出版日期2011-4-1