The greatest fold-change difference in ESR1-depleted recurrences was the upregulation of PROM1. PROM1 is a marker for tumor-initiating cancer stem cells and plays a key role in determining ER-positive luminal cell fate during differentiation from multipotent stem cells [56], suggesting long-term endocrine-deprived breast cancer cells may enrich themselves with stem-like progenitors to achieve estrogen independence. Here, ESR1 is linked to cancer.