Abstract
Dysregulation of miRNAs is important in breast cancer initiation and malignant progression. Recently we showed that miR-152 downregulation is associated with breast cancer development, yet the underlying mechanism of miR-152 remains to be well elucidated. In this study, we identified β-catenin as a new direct target of miR-152. MiR-152 inhibited cell proliferation by targeting and inhibiting both β-catenin and PKM2 expression. We found that miR-152 expression sensitized the breast cancer cells to paclitaxel treatment by inhibiting β-catenin and PKM2 expression. Intriguingly, IGF-1 induced β-catenin and PKM2 expression and enhanced β-catenin and PKM2 interaction. Subsequently, IGF-1-induced β-catenin and PKM2 complex translocated into the nucleus, which in turn activated expression of miR-152. These results suggested a regulatory circuit between miR-152, β-catenin and PKM2 in breast cancer. By using human clinical specimens, we also showed that miR-152 expression levels were negatively correlated with β-catenin and PKM2 levels in breast cancer tissues. Our findings provide new insights into a mechanism of miR-152 involved in β-catenin and PKM2 inhibition which would have clinical implication for the cancer development and new treatment option in the future.
Highlights
Breast cancer is the most frequent type of cancer in women[1]
Except for DNA methyltransferase 1 (DNMT1), accumulating evidence indicates that miR-152 targets on multiple oncogenes like PKM2, IRS-1 and IGF-1R in human breast cancer, and inhibits a variety of cellular functions, including proliferation, angiogenesis and migration, suggesting that miR-152 may potentially function as a tumor suppressor in breast cancer[8,10,14]
The IGF signaling contains a dynamic network of proteins including ligands, their associated receptors (IGF-1R and IGF-2R) and several IGF binding proteins (IGFBPs) that participate in the regulation of human cancer development[25]
Summary
Breast cancer is the most frequent type of cancer in women[1]. the 5-year relative survival rate for female breast cancer patients has improved due to both improvements in breast cancer treatment and early detection, breast cancer is still the second leading cause of cancer deaths[2]. We aim to address the following questions: (1) Whether β-catenin is direct target of miR-152 in breast cancer; (2) whether miR-152 overexpression inhibits cell proliferation by inhibiting both β-catenin and PKM2 expression; (3) what is role of miR-152 in breast cancer resistance to paclitaxel treatment; (4) whether miR-152 is involved in IGF-1-induced β-catenin and PKM2 expression. The answer of these questions would provide new insights into a better understanding of the role of miR-152 in breast cancer development
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