Acquired differentiation and loss of malignancy of spontaneous pulmonary metastases in human-in-mouse breast cancer models
Menée à l'aide de modèles murins de cancer du sein, cette étude met en évidence des mécanismes par lesquels un micro-ARN (miR-138) favorise la disparition de micrométastases pulmonaires
Patient-derived human-in-mouse breast tumor xenograft models with spontaneous lung metastases have emerged as powerful, representative systems of cancer metastasis. To evaluate the malignancy of lung micro-metastases, we implanted pulmonary metastatic cells into mouse mammary fat pads. Compared to the parental breast tumors, the lung met-derived mammary tumors showed a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Combined microRNA and gene array analyses characterized the acquired epigenetic features. The lung met-derived model displayed differential expression profiles of a few hundred genes and microRNAs, including negative regulators of cell proliferation and metabolism, promoters of mammary epithelial differentiation, and unknown regulators. The lung-met-derived gene signature correlated with clinical breast tumor subtypes. Subsequently, we identified microRNA-138 as a novel regulator of breast cancer cell invasion and EMT by directly targeting EZH2, a polycomb epigenetic regulator. GATA3 transcriptionally regulates miR-138 levels in the lung metastases. The miR-138 activity signature defined from the microarray gene expression analyses serves as a novel independent prognostic marker for breast cancer survival beyond the classical pathological variables (tumor size, nodal status, grade, age, and systemic treatment), intrinsic subtypes, and a proliferation gene signature. Our results highlight the loss of malignancy of some lung micro-metastatic lesions and the epigenetic regulation of this phenotype.