Breast cancer is the most prevalent type of malignancy in women with ∼1.7 million new cases diagnosed annually, of which the majority express ERα (ESR1), a ligand-dependent transcription factor. Genome-wide chromatin binding maps suggest that ERα 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 ERα-positive breast cancer cell proliferation. We validated several candidates, including CUTE, a putative ERα-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 ERα-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 ERα in breast cancer. Thus, CUEDC1 is a functional target gene of ERα and is required for breast cancer cell proliferation.

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Keywords Breast, Cancer, CRISPR-Cas9, Enhancer
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Journal Cancer Letters
Lopes, R.F.M, Korkmaz, G, Revilla, S.A. (Sonia Aristin), van Vliet, R. (Romy), Nagel, C.R, Custers, L. (Lars), … Agami, R. (2018). CUEDC1 is a primary target of ERα essential for the growth of breast cancer cells. Cancer Letters, 436, 87–95. doi:10.1016/j.canlet.2018.08.018