An epithelial-mesenchymal-amoeboid transition gene signature reveals molecular subtypes of breast cancer progression and metastasis

Cancer cells within a tumor are known to display varying degrees of metastatic propensity but the molecular basis underlying such heterogeneity remains unclear. We analyzed genome-wide gene expression data obtained from primary tumors of lymph node-negative breast cancer patients using a novel metastasis biology-based Epithelial-Mesenchymal-Amoeboid Transition (EMAT) gene signature, and identified molecularly distinct subtypes associated with distinct prognostic profiles. EMAT subtype status improved prognosis accuracy of clinical parameters and statistically outperformed traditional breast cancer intrinsic subtypes. Additionally, analysis of 3D spheroids from an in vitro isogenic model of breast cancer progression reveals that EMAT subtypes display progression from premalignant to malignant and pre-invasive to invasive cancer. EMAT classification is a biologically informed method to assess metastasis risk in early stage, lymph node-negative breast cancer patients and appears to molecularly reconcile conflicting paradigms of breast cancer metastasis.