TY  - JOUR
A1  - Blanchard, Zannel
A1  - Vahrenkamp, Jeffery M.
A1  - Berrett, Kristofer C.
A1  - Arnesen, Spencer
A1  - Gertz, Jason
T1  - Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer
Y1  - 2019/09/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1429 
EP  - 1441 
DO  - 10.1101/gr.244780.118 
VL  - 29 
IS  - 9 
UR  - http://genome.cshlp.org/content/29/9/1429.abstract 
N2  - Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy–resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wild-type ESR1. The D538G mutation impacted expression, including a large set of nonestrogen-regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is distinct from constitutive ESR1 activity because mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, the D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells. 
ER  -