title: Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer.
abstract: 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.
authors.affiliation: Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yun-Yong
authors.initials: YY
authors.lastname: Park
authors.forename: Kyounghyun
authors.initials: K
authors.lastname: Kim
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Kim
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.forename: Jae Yun
authors.initials: JY
authors.lastname: Lim
authors.forename: Jane
authors.initials: J
authors.lastname: Li
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Woojin
authors.initials: W
authors.lastname: Jeong
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C403073:NR2E3 protein, human; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D013629:Tamoxifen