Using the synthetic tumor microenvironment mimics (STEMs)—a spheroid system composed of breast cancer cells (BCC) with defined human MSC and EC fractions, here we show that EC organization into vascular structures is BC phenotype dependent, and independent of ERα expression in epithelial cancer cells, and involves MSC-mediated Notch1 signaling. The gene discussed is ESR1; the disease is breast carcinoma.