Inherited variation in miR-290 expression suppresses breast cancer progression by targeting the metastasis susceptibility gene Arid4b
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en interagissant avec le gène Arid4b, le micro-ARN 290 réprime le processus métastatique d'un cancer du sein
The metastatic cascade is a complex and extremely inefficient process with many barriers. Understanding this process is of critical importance since most cancer mortality is associated with metastatic disease. Recently, it has become evident that certain microRNAs (miRNAs) control metastasis, yet few studies have examined how germline variations that dysregulate these miRNAs may affect metastatic potential. To explore this possibility, highly metastatic MMTV-PyMT mice were crossed with AKXD (AKR/J x DBA/2J) recombinant inbred strains to produce F1 progeny with varying metastatic indices. When mammary tumors from the F1 progeny were analyzed by miRNA microarray, miR-290 (containing miR-290-3p and miR-290-5p) was identified as a top candidate for a progression-associated miRNA. Microarray results were validated in vivo by demonstrating miR-290 upregulation in breast cancer cells suppressed both primary tumor and metastatic growth. Computational and transcriptional reporter analyses identified breast cancer progression gene Arid4b as a top target of miR-290-3p. Notably, pathway analysis identified estrogen receptor (ER) signaling as the top canonical pathway affected by miR-290 upregulation. ER levels were elevated in miR-290-expressing tumors and positively correlated with apoptosis. Taken together, our results suggested that miR-290 targets Arid4b while simultaneously enhancing ER signaling and increasing apoptosis, thereby suppressing metastatic progression. Our findings illustrate how inherited differences in miRNA expression affect breast cancer progression.