MicroRNA-9 is associated with epithelial-mesenchymal transition, breast cancer stem cell phenotype, and tumor progression in breast cancer

Abstract

MicroRNAs (miRNAs) are involved in the progression of breast cancer. Some miRNAs, especially the miR-200 family, miR-9, and miR-155 have been reported to be associated with epithelial-mesenchymal transition (EMT) and breast cancer stem cell (BCSC) phenotypes. This study was designed to evaluate the expression levels of these miRNAs in human breast cancer samples and analyzed their relationship with clinicopathologic features of the tumor including breast cancer subtype, EMT, BCSC phenotype, and prognosis. Expression levels of the miR-200 family, miR-9, and miR-155 were quantified using qRT-PCR. Breast cancer subtype, BCSC phenotype (CD44+/CD24- and ALDH1+), and expression of EMT markers (vimentin expression and E-cadherin loss) were evaluated by immunohistochemistry. miR-9 was more highly expressed in HER2+ and triple-negative subtypes than in luminal subtypes. Its expression level was significantly higher in tumors with high T stage, high histologic grade, p53 overexpression, and high proliferation index. Expression of miR-9 was also higher in tumors showing the CD44+/CD24- phenotype, vimentin expression, and E-cadherin loss. Furthermore, high level of miR-9 expression was found to be an independent prognostic factor for poor disease-free survival of the patients. Expression of miR-200a and miR-141 was highest in luminal A subtype, and miR-155 expression was highest in triple-negative subtype. Although the expression levels of some miR-200 family members and miR-155 showed difference with regard to EMT or BCSC phenotype, they were not associated with patients' prognosis. In conclusion, overexpression of miR-9 is found in tumors with aggressive phenotypes and is associated with poor prognosis in breast cancer, suggesting that it may serve as a potential biomarker for breast cancer progression and a target for treatment.

miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer

“…miR-9 has a well-recognized prometastatic function in human breast cancer (10,23), and it has been more recently associated with poor prognosis, EMT, and stemness features (11). Consistently, we found that higher miR-9 expression identified breast cancer patients with poor prognosis and associated with high histologic grade.…”

“…Together with the internalization and degradation of PDGFRb upon stimulation, this provides a mechanism by which signaling through this receptor may be temporally limited. High levels of miR-9 have been associated with prometastatic function in human breast cancer (10), as well as with the acquisition of a mesenchymal and aggressive phenotype (11). On the other hand, members of the miR-200 family (five miRNAs organized in two clusters: miR200a/b/429 and miR-200c/141) are well-known negative regulators of EMT due to their direct targeting of several transcriptional factors implicated in the transition, such as ZEB1/2 and Snail (12).…”

Biomarkers for EMT and MET in breast cancer: An update

“…Downregulation of miR-9-mediated E-cadherin expression results in the activation of β-catenin signaling, which contributes to the upregulation of VEGF; in turn, this leads to increased tumor angiogenesis (80). Overexpression of miR-9 is also found in tumors with aggressive phenotypes, and is related to poor prognosis in breast cancer, suggesting that it may serve as a potential biomarker for the progression of breast cancer as well as a target for treatment (81).…”

Noncoding RNAs in breast cancer

“…Patients with basal-like breast cancers frequently have poor prognosis, and are difficult to treat owing to the frequent lack of hormone receptors (a triple-negative phenotype with loss of ER and PR, and no HER2 amplification) that can be therapeutically targeted [138][139][140]. Six of these 16 basal-related miRNAs have been reported to be associated with basal-like/triple-negative breast cancer, including miR-9, miR-18 a, miR-19 a, miR-93, miR-106 b and miR-126 [141][142][143][144][145][146]. Noticeably, three miRNAs (miR-126, miR-143, miR-210) implicated in the DCIS-to-IDC transition are specifically dysregulated in basal-like IDC, suggesting that their deregulation plays a critical role in driving the progression of DCIS lesions to malignant basal-like IDC tumors (Table 2) Among luminal subtypes, luminal-B is a more aggressive subtype than luminal-A owing to low/negative expression of PR and/or HER2 overexpression, and high proliferation indicated by high Ki-67 [148].…”