Loss of malignancy of the spontaneous pulmonary metastasis in a human-in-mouse breast cancer model

Patient-derived human-in-mouse breast tumor xenograft models with spontaneous lung metastases1 have emerged as a powerful system to characterize and target cancer metastasis. To evaluate the malignancy of metastatic lesions in the mouse lungs, we implanted the pulmonary metastatic cells into the mouse mammary fat pads. Surprisingly, compared to the parental tumor model, the lung met-derived model showed a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Then we characterized the genetic and epigenetic features acquired by the lung met-derived breast tumor model, combining microRNA/gene array analyses with RNA-sequencing. The lung met-derived model displayed differential expression profiles of a few hundred genes and many microRNAs, whereas the RNA sequencing data identified an overall increase of single nucleotide alternations in the 3’UTRs of genes, possibly subject to microRNA regulations. Subsequently, we identified microRNA-138 as a regulator of invasion and epithelial-mesenchymal transition (EMT) by directly targeting EZH2, a polycomb epigenetic regulator. Our results highlight the importance of epigenetic regulation by microRNAs and genes in regulating breast cancer invasion and EMT. reference x sample