RT Journal Article
SR Electronic
T1 ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 617142
DO 10.1101/617142
A1 Adriana C. Rodriguez
A1 Jeffery M. Vahrenkamp
A1 Kristofer C. Berrett
A1 Kathleen A. Clark
A1 Katrin P. Guillen
A1 Sandra D. Scherer
A1 Chieh-Hsiang Yang
A1 Bryan E. Welm
A1 Margit M. Janát-Amsbury
A1 Barbara J. Graves
A1 Jason Gertz
YR 2019
UL http://biorxiv.org/content/early/2019/04/23/617142.abstract
AB Estrogen signaling through estrogen receptor alpha (ER) plays a major role in endometrial cancer risk and progression; however, the molecular mechanisms underlying ER’s regulatory role in endometrial cancer are poorly understood. In breast cancer cells, ER genomic binding is enabled by FOXA1 and GATA3, but the transcription factors that control ER genomic binding in endometrial cancer cells remain unknown. We previously identified ETV4 as a candidate factor controlling ER genomic binding in endometrial cancer cells and here we explore the functional importance of ETV4. Homozygous deletion of ETV4, using CRISPR/Cas9, led to greatly reduced ER binding at the majority of loci normally bound by ER. Consistent with the dramatic loss of ER binding, the gene expression response to estradiol was dampened for most genes. ETV4 contributes to estrogen signaling in two distinct ways; ETV4 loss impacts chromatin accessibility at some ER bound loci and impairs ER nuclear translocation. The diminished estrogen signaling upon ETV4 deletion led to decreased growth, particularly in 3D culture where hollow organoids were formed. Our results show that ETV4 plays a necessary role in estrogen signaling in endometrial cancer cells.