Journal
CANCER LETTERS
Volume 436, Issue -, Pages 87-95Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.08.018
Keywords
Cancer; Enhancer; Breast; CRISPR-Cas9
Categories
Funding
- Fundacao para a Ciencia e Tecnologia de Portugal [SFRH/BD/74476/2010]
- funds of enh Reg ERC-AdG [322493]
- NWO [NGI 93512001/2012]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/74476/2010] Funding Source: FCT
- European Research Council (ERC) [322493] Funding Source: European Research Council (ERC)
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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.
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