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Abstract
MicroRNAs as a class of novel negative regulators have drawn intensive attention since their existence in mammals was discovered in 2001. As endogenous small non-coding RNAs, miRNAs are capable of silencing gene expression at the post-transcriptional level by translation blocking or/and mRNA degradation. MicroRNA has been reported to involve in diverse biological events. Although miRNA deregulation has been observed in many types of cancers including breast cancer, only few of these de-regulated miRNAs have been confirmed to be related with breast cancer progression. This study is to investigate the association of miRNAs with the development of breast cancer.
In this study, we report that mir-205 is significantly under-expressed in breast tumors compared to the matched normal breast tissues. Similarly, breast cancer cell lines including MCF-7 and MDA-MB-231 express a much lower level of mir-205 than the non-malignant MCF-10A cells. Of interest, ectopic expression of mir-205 significantly inhibits cell proliferation and anchorage-independent growth as well as cell invasion. Furthermore, mir-205 was shown to suppress lung metastasis in a mouse model. Finally, western blot combined with the luciferase reporter assays demonstrated that ErbB3 and vascular endothelial growth factor A (VEGF-A) are direct targets of mir-205 and such mir-205-mediated suppression is likely through the direct interaction with the putative mir-205 binding site in the 3’-untranslated region (3-UTR) of ErbB3 and VEGF-A, suggesting that down-regulation of ErbB3 and VEGFA likely contributes to the suppression role of mir-205 in breast cancer cells. Together, these results suggest that mir-205 is a tumor suppressor in breast cancer.
Given that mir-205 is downregulated in breast tumor specimens and breast cancer cell lines, it would be interesting to determine how mir-205 is regulated in cancer cells. Supprisingly, we found that agents which have been previously shown to induce other miRNAs, such as p53 induction, the phenolic compound kaempferol, hypoxia, and ROS stress have little effect on mir-205 expression, whereas de-methylation and UV treatment only a moderate effect on mir-205 .
Therefore, our studies indicate that mir-205 is a tumor suppressor in breast cancer progression, however, regulation of mir-205 still remains to be elucidated. Knowledge gained from these studies will provide more comprehensive understanding of how miRNAs are associated with tumor initiation and progression in breast cancer and how miRNAs are de-regulated during cancer development, and as a result, mir-205 may serve as a novel target for cancer therapy.
