Suppression of miRs-497/195 axis possibly confers endocrine therapy resistance via elevated expression of FLT4 and the noncoding RNA MIR503HG

Abstract

Endocrine therapy resistance (ETR) in breast cancer is achieved by decreasing expression or acquiring mutations in ER, dysregulating cell cycle genes, and/or ER co-activators/co-repressors. We reported that high expression of JMJD6 induced ETR by depleting ER. In this study, RNA-sequencing of parental MCF7, Tamoxifen resistant (TAMR), Long-term Estrogen deprived (LTEDI), and Jumonji domaining containing protein 6 (JMJD6) overexpressing (JOE) cells was carried out. 170 differentially expressed genes common to all cells were found, of which 73 maintained the same directionality in expression. Pathway based curation identified 7 up- and 14 down-regulated genes spanning multiple cancer pathways. These genes were used for CNC and ceRNA network construction and a triad FLT4:MIR503HG:miR497/195/424 was discovered in TAMR-LTED cells, but triads were rare in JOE cells. ER expressing cells probably devise a complex ceRNA based mechanism for ETR establishment, whereas lowering ER is sufficient in JOE cells. Further, the clustering of TCGA samples based on the expression of upregulated ETR genes led to the bifurcation of ER+ tumors into two groups, one intermixing with ER- tumors and showing poorer survival. Of the 7 up genes, B3GNT3, ADORA2B, SLC2A3, and FLT4 showed high expression in ETR models and normal breast but lower expression in tumors. We suggest that re-expression of these genes occurs during therapeutic intervention leading to poorer outcome. In addition to these 4 genes, testing for ER, MIR503HG, miR497, miR195, and miR424 expression could be useful in ETR prediction.