Tumourigenesis is associated with a network of abnormal genes expression. The genes expression patterns and their role are substantially different with specific tumour types. Confirming each factor in the network may promote precise medical treatment. To extend our previous study, we focused on the regulatory miRNAs of ETV1 in TNBC. In this study, we found that ETV1 was a direct target of miR-17-5p. Given the observation that miR-17-5p was down-regulated in TNBC cell lines and clinical tumour tissues in contrast to ETV1, we speculated that up-regulation of miR-17-5p would suppress triple-negative breast tumour cell oncogenic activity by targeting ETV1 and dysregulation of miR-17-5p would be associated with the prognosis of TNBC patients.
miR-17-5p has been linked to tumourigenesis in a broad range of cancers, including hepatocellular carcinoma [
19], gastric cancer [
20], ovarian cancer [
21], prostate cancer [
22], and breast cancer [
23,
24]. The abundance and function of miR-17-5p vary with tumour type, even if observed in same tumour type. Overexpression of miR-17-5p inhibits hormone-dependent breast cancer cell proliferation by targeting AIB1 or cyclin D1 [
16,
25]. A systematic analysis showed that down-regulation of miR-17-5p may be a prerequisite for the onset of TNBC metastasis mediated by TGFβ [
26]. However, conflicting data have been reported [
27,
28]. We suppose that the partial reason may be tumour heterogeneity. In this study, we showed that miR-17-5p expression levels were significantly down-regulated in TNBC cell lines and clinical tumour tissues. We hypothesize that miR-17-5p decrease in TNBC might be associated with c-Myc or p53 abnormal activity [
29,
30]. We observed that enhancement of miR-17-5p in TNBC cells significantly inhibited cell proliferation, migration and invasion. Lower miR-17-5p expression was related to a shorter survival time of TNBC patient. miR-17-5p is a independent favourable prognostic factor for TNBC patient. The results support that miR-17-5p may function as a tumour suppressor in TNBC, which is consistent with the literature [
26].
ETV1 contributes to tumourigenic activity through activation of MMP, COX-2 and VEGF expression [
3,
4,
31,
32]. Studies in our group demonstrated that ETV1 acts as an oncogene in TNBC, and may be an independent, poor prognostic predictor of the patients [
6]. Highly expressed miR-17 enhances melanoma cell motility and migration by repressing translation of the ETV1 protein, which may support the development of metastasis [
9]. However, the miR-17 level is significantly lower in GIST. Up-regulation of miR-17 in GIST cell lines inhibits cell proliferation by degrading ETV1 mRNA, which may suppress the tumour progression [
12]. These results suggest that one miRNA may function as an oncogene or tumour suppressor gene in a cell type- and context-dependent manner, even if it targets same gene [
11]. In the present study, an inverse expression pattern of miR-17-5p and ETV1 in TNBC cell lines and tumour tissues was detected. To reinforce the expression of miR-17-5p in TNBC cell lines not only significantly reduced the expression of ETV1 but also inhibited cell proliferation, migration and invasion, which might suppress the development of TNBC. Moreover, rescue of ETV1 expression in the presence of miR-17-5p significantly restore the cell phenotype. These results indicate that miR-17-5p may influence the behavior of TNBC by regulating ETV1 expression. This was further supported by an in vivo trial using a well-established zebrafish metastatic model. Our results suggest that there might exist a signaling pathway, c-Myc/p53—miR-17-5p—ETV1—MMP, COX-2 and VEGF [Fig.
7B], playing a role in TNBC development [
3,
6,
29]. In addition, overexpression of COP1 can significantly reduce the level of ETV1, and turnover TNBC cell phenotype [
6,
33]. The mutual phenomenon is the relatively low abundance of COP1 and miR-17-5p in TNBC, which might be the source of TNBC occurrence. Therefore, whether the joint overexpression of both miR-17-5p and COP1 or other suppressor genes is a new strategy for TNBC therapy by targeting ETV1 needs further research. In addition to miR-17-5p, other members of the miR-17-92 cluster, such as miR-19a/b, etc., which are also dysregulated in TNBC, have potential binding sites in ETV1. Future study may clarify whether these miRNAs are involved in modifying TNBC characteristics by targeting ETV1. Recently, cancer stem cells (CSCs) have been suggested as a cause of metastasis and recurrence in breast cancer [
34]. To confirm the same modulatory mode between miR-17-5p and ETV1 existing in CSC from TNBC cells would be essential for achieving long term therapeutic success for TNBC patients by targeting these rare cells.