Using variant estrogen receptor alpha-positive (ERα+ MCF-7) breast tumor xenografts with constitutive active Raf-1/MAPK signaling (vMCF-7Raf-1), we showed that metastatic cancer cells display a clonal origin and increased expression of NOTCH3 that is required to induce self-renewal, stemness, and high invasive capacity. The gene discussed is NOTCH3; the disease is cancer.