MicroRNAs (miRNAs) are a large family of small non-coding RNAs that negatively regulate protein-coding gene expression post-transcriptionally via base pairing between the 5’seed region of a miRNA and the 3’ untranslated region (3’UTR) of a target messenger RNA (mRNA). Recent studies have shown that miRNAs play a critical role in many diseases, including cancer. The microRNA-200 (miR-200) family consists of 5 members (miR-200a, -200b, -200c, -141, and -429) and has recently emerged as a prominent player in cancer initiation, progression, and metastasis. Studies also suggest that the miR-200 family could be a potential therapeutic for the treatment of cancer. Even though the role of the miR-200 family in cancer has recently been greatly studied, the role of this family on cancer metastasis continues to be controversial. Furthermore, many of these studies focus on the role of the entire family or an entire cluster of the miR-200 family in cancer metastasis and not the role of individual members of the family. Therefore to better understand the disease, this family, and to discover novel therapeutics, it is important to elucidate the role that each member of the miR-200 family plays in cancer metastasis.Breast cancer is the most diagnosed cancer and second leading cause of cancer related death in women in the United States. Breast cancer can be classified into three main subtypes: luminal, Her2+, and triple negative. These subtypes are clinically defined by receptor status; luminal is defined by the presence of the estrogen receptor (ER), Her2+ by human epidermal growth factor receptor 2 (Her2) amplification, and triple negative by the absence of the estrogen receptor, progesterone receptor (PR), and Her2 amplification. Triple negative breast cancer (TNBC) is a unique subtype of breast cancer that is often a highly invasive and metastatic form of breast cancer. TNBC has also been shown to have an overall poorer prognosis compared with other breast cancer subtypes. This is partly due to the inherent aggressiveness of TNBC and partly because it lacks effective targeted therapies. Therefore, chemotherapy is currently the only treatment option for metastatic TNBC and is only effective at the initial treatment stage. Consequently, there is an urgent need to better understand the underlying mechanism of TNBC aggressive behavior and identify novel targets for developing more efficient therapies for TNBC.This study was performed to investigate the effect and mechanism of miR-200b on TNBC metastasis and identify targets for developing more efficient treatment for TNBC. We found that miR-200 expression was significantly reduced in the highly migratory and invasive, mesenchymal-like TNBC cells compared to other breast cancer subtypes. Expressing miR-200b in two of these highly migratory and invasive TNBC cells, MDA-MB-231 and SUM-159, dramatically reduced cell migration and lung metastasis in a mouse mammary xenograft tumor model. In this study we identified PKCα and ARHGAP18 as novel direct targets of miR-200b, and these proteins are inversely correlated with miR-200b expression in breast cancer cells. Furthermore, reduction of PKCα or ARHGAP18 protein expression significantly impaired the migratory capability of MDA-MB-231 and SUM-159 TNBC cells, and enforced expression of PKCα or ARHGAP18 impairs the inhibitory effect of miR-200b on cell migration and lung metastasis. Mechanistic studies revealed that miR-200b affects cell migration and lung metastasis by regulating key regulators of the actin cytoskeleton, Rac1 and RhoA. Overall, this study suggests that these proteins could serve as novel therapeutic options for the treatment of aggressive and metastatic TNBC.
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