Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer

Abstract

The purpose of this study is to identify metastasis- associated genes/signaling pathways in basal-like breast tumors. Kaplan–Meier analysis of two public meta-datasets and functional classification was used to identify genes/signaling pathways significantly associated with distant metastasis free survival. Integrated analysis of expression correlation and interaction between mRNAs and miRNAs was used to identify miRNAs that potentially regulate the expression of metastasis-associated genes. The novel metastatic suppressive role of miR-17-5p was examined by in vitro and in vivo experiments. Over 4,000 genes previously linked to breast tumor progression were examined, leading to identification of 61 and 69 genes significantly associated with shorter and longer DMFS intervals of patients with basal-like tumors, respectively. Functional annotation linked most of the pro-metastatic genes to epithelial mesenchymal transition (EMT) process and three intertwining EMT-driving pathways (hypoxia, TGFB and Wnt), whereas most of the anti-metastatic genes to interferon signaling pathway. Members of three miRNA families (i.e., miR-17, miR-200 and miR-96) were identified as potential regulators of the pro-metastatic genes. The novel anti-metastatic function of miR-17-5p was confirmed by in vitro and in vivo experiments. We demonstrated that miR-17-5p inhibition in breast cancer cells enhanced expression of multiple pro-metastatic genes, rendered cells metastatic properties, and accelerated lung metastasis from orthotopic xenografts. In contrast, intratumoral administration of miR-17-5p mimic significantly reduced lung metastasis. These results provide evidence supporting that EMT activation and IFN pathway inactivation are markers of metastatic progression of basal-like tumors, and members of miR-17, miR-200, and miR-96 families play a role in suppressing EMT and metastasis. The metastasis-associated genes identified in this study have potential prognostic values and functional implications, thus, can be exploited as therapeutic targets to prevent metastasis of basal-like breast tumors.

Finding associations in a heterogeneous setting: Statistical test for aberration enrichment

“…TAOK1 had a relatively low p-value by Limma (E-04) but the 3 other associations are specific to our test and correspond to low values of r . TAOK1 was previously listed as a metastasis-associated genes in basal-like breast tumors [18] (through expression). RALB , also known as RAS Like Proto-Oncogene B, which is known for its role in invasion and metastasis across cancers and specifically for breast cancer [76].…”

Exercise and weight loss interventions and miRNA expression in women with breast cancer

“…We identified eight miRNAs significantly associated with BMI with the strongest positive associations as miR_22_3p(r=0.26, p=0.004) and miR_122_5p(r=0.25, p =0.005), both of which are implicated in BC metabolism 63–65 . miRNAs with the strongest negative BMI association was miR_191_5p(r=−0.22, p =0.016) and miR_17_5p(r=−0.22, p =0.017), which are implicated in BC progression 66, 67 .…”

Downregulation of microRNA-17-5p inhibits drug resistance of gastric cancer cells partially through targeting p21

“…Studies have indicated that the function of miR-17-5p appears to be conflicting in different cancer cell types. Fan et al (27) reported that miR-17-5p serves a role in suppressing epithelial mesenchymal transition and metastasis in breast cancer cells. However, another study demonstrated that the downregulation of miR-17-5p contributes to the resistance of lung cancer cells to paclitaxel (28).…”