Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer
Yun-Yong Park ; Kyounghyun Kim ; Ju-Seog Lee ; Stephen Safe ; Gordon B. Mills ; Woojin Jeong ; Ana Maria Gonzalez-Angulo ; Yiling Lu ; Jane Li ; Jae Yun Lim ; Eun Sung Park ; , Soo Mi Kim ; Bryan T. Hennessy ; Sang-Bae Kim
EMBO Molecular Medicine, Vol.4(1) : 52~67, 2011
EMBO Molecular Medicine
ESR1 is one of the most important transcription factors and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered a potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to the promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and a favourable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insights on the regulation of ESR1 by NR2E3 and the clinical relevance of NR2E3 in breast cancer.