Fig. 11

AURKA^high/NOTCH3^high breast tumor metastasis-initiating cells (BT-MICs) promote cancer cell seeding and metastatic growth. Primary breast tumors show heterogeneous subclones where the majority of cancer cells exhibit an AURKA^low/NOTCH3^low phenotype with low invasive capacity. Increased expression and activity of Aurora kinase A (AURKA) during tumor growth will induce epithelial-mesenchymal transition (EMT) and the genesis of AURKA^high/NOTCH3^low BTIC subclones with increased invasive capacity but incapable of giving rise to distant metastases. Gain of NOTCH3 expression in AURKA^high/NOTCH3^high BTICs will lead to the clonal expansion of AURKA^high/NOTCH3^high BT-MICs that will successfully complete the invasion-metastasis cascade. Pharmacologic inhibition of NOTCH3 signaling with either pan-NOTCH inhibitors or humanized monoclonal antibodies will halt AURKA^high/NOTCH3^high BT-MICs seeding to secondary organs and metastatic growth