Inhibition of Triple Negative Breast Cancer Metastasis by microRNA-200b

Triple negative breast cancer (TNBC) refers to a group of highly diverse tumors that do not have detectable levels of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, accounting for 10-20% of newly diagnosed breast cancer cases. Compared to other subtypes of breast cancer, TNBCs usually have more aggressive metastasis and are associated with much worse outcomes. Unfortunately, the mechanism of TNBC aggressive metastatic behavior has been poorly understood. No efficient targeted therapies for TNBC are now available. Therefore, there is a clear and urgent need for identifying TNBC-specific molecular targets. The goal of this study is to identify molecular drivers of TNBC metastatic behavior through dissecting the mechanism by which microRNA-200b inhibits TNBC lung metastasis using live animal imaging system to dynamically monitor the metastasis, which will lead to the development of efficient targeted therapies for TNBC. MicroRNAs (miRNAs) are a large class of small non-coding RNA molecules that down-regulate protein coding gene expression. Studies have shown that the levels of many miRNAs are altered in various types of cancers including breast cancer. It was found that some miRNAs have anti-cancer effects suppressing cancer metastasis; however, how miRNAs exhibit their effects on cancer metastasis is largely unclear. One family of miRNAs that has been shown to have anti-cancer potential is the miRNA-200 family consisting of 5 members (miR-200b/a/429/c/141) as their levels were reduced in many types of cancer. Our preliminary studies found: (i) miR-200 levels are extremely lower in invasive TNBC cells and metastatic TNBC tumors than other types of breast cancer. (ii) Enforced expression of miR-200b in invasive TNBC cells reduces their proliferation and motility, inhibits mouse mammary tumor blood vessel formation and completely blocks lung metastasis. (iii) Bioinformatic analysis and quantitative PCR measurement indicate that two genes Rho GTPase activating protein 19 (ARHGAP19) and integrin a9 (ITGA9) could be miR-200b potential targets. Furthermore, (iv) breast cancer online data base analysis showed that patients who have higher levels of ARHGAP19 and ITGA9 are associated with significant worse distant metastasis free survivals, suggesting crucial roles of these two genes In breast cancer metastasis. We hypothesize that miR-200b inhibits TNBC metastasis by targeting ARHGAP19 and ITGA9. To test this hypothesis, we propose three specific aims to examine: (1) whether ARHGAP19 plays a role in the inhibitory effect of miR-200b on TNBC cell proliferation, migration, invasion and tumor metastasis; (2) whether ITGA9 plays a role in the inhibitory effect of miR-200b on TNBC cell proliferation, migration, invasion and tumor metastasis; and (3) whether inhibiting miR-200b function makes non-metastatic TNBC tumors become metastatic. Our findings may lead to the development of novel therapies for TNBC.