CUEDC1 is a primary target of ERα essential for the growth of breast cancer cells

Breast cancer is the most prevalent type of malignancy in women with similar to 1.7 million new cases diagnosed annually, of which the majority express ERa (ESR1), a ligand-dependent transcription factor. Genome-wide chromatin binding maps suggest that ER alpha may control the expression of thousands of genes, posing a great challenge in identifying functional targets. Recently, we developed a CRISPR-Cas9 functional genetic screening approach to identify enhancers required for ER alpha-positive breast cancer cell proliferation. We validated several candidates, including CUTE, a putative ER alpha-responsive enhancer located in the first intron of CUEDC1 (CUE-domain containing protein). Here, we show that CUTE controls CUEDC1 expression, and that this interaction is essential for ER alpha-mediated cell proliferation. Moreover, ectopic expression of CUEDC1, but not a CUE-domain mutant, rescues the defects in CUTE activity. Finally, CUEDC1 expression correlates positively with ER alpha in breast cancer. Thus, CUEDC1 is a functional target gene of ER alpha and is required for breast cancer cell proliferation.