| Summary: | Breast cancer cells with mesenchymal characteristics, particularly the claudin-low subtype, express extremely low levels of miR-200s. Therefore, this study examined the functional impact of restoring miR-200 expression in a human claudin-low breast cancer cell line MDA-MB-231. MDA-MB-231 cells were stably transfected with a control vector (MDA-231EV) or the miR-200c/141 cluster (MDA-231c141). Injection of MDA-231c141 cells into the 4th mammary gland of NCG mice produced tumors that developed significantly slower than tumors produced by MDA-231EV cells. Spontaneous metastasis to the lungs was also significantly reduced in MDA-231c141 cells compared to MDA-231EV cells. RNA sequencing of MDA-231EV and MDA-231c141 tumors identified genes including <i>MXRA8</i> as being downregulated in the MDA-231c141 tumors. <i>MXRA8</i> was further investigated as elevated levels of <i>MXRA8</i> were associated with reduced distant metastasis free survival in breast cancer patients. Quantitative RT-PCR and Western blotting confirmed that <i>MXRA8</i> expression was significantly higher in mammary tumors induced by MDA-231EV cells compared to those induced by MDA-231c141 cells. In addition, MXRA8 protein was present at high levels in metastatic tumor cells found in the lungs. This is the first study to implicate <i>MXRA8</i> in human breast cancer, and our data suggests that miR-200s inhibit growth and metastasis of claudin-low mammary tumor cells in vivo through downregulating <i>MXRA8</i> expression.
|
|---|