title: The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells.
abstract: Estrogen receptor-α (ER) is expressed in the great majority of breast cancers, and the inhibition of ER action is a key part of breast cancer treatment. The inhibition of ER action is achieved using anti-estrogens, primarily tamoxifen, and with aromatase inhibitors that inhibit estrogen biosynthesis, thereby preventing ER activation. However, resistance to these therapies is common. With the aim of identifying new molecular targets for breast cancer therapy, we have identified the liver receptor homolog-1 (LRH-1) as an estrogen-regulated gene. RNA interference and over-expression studies were used to investigate the role of the LRH-1 in regulating breast cancer growth and to identify the targets of an LRH-1 action. Promoter recruitment was determined using reporter gene and chromatin immunoprecipitation (ChIP) assays. We show that LRH-1 regulates breast cancer cell growth by regulating the ER expression. Reporter gene and in vitro DNA-binding assays identified an LRH-1-binding site in the ER gene promoter, and ChIP assays have demonstrated in vivo binding at this site. We also provide evidence for new LRH-1 variants in breast cancer cells arising from the use of alternative promoters. Previous studies have shown that LRH-1 functions in estrogen biosynthesis by regulating aromatase expression. Our findings extend this by highlighting LRH-1 as a key regulator of the estrogen response in breast cancer cells through the regulation of ER expression. Hence, inhibition of LRH-1 could provide a powerful new approach for the treatment of endocrine-resistant breast cancer.
authors.affiliation: Department of Oncology, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Paul T R
authors.initials: PT
authors.lastname: Thiruchelvam
authors.forename: Chun-Fui
authors.initials: CF
authors.lastname: Lai
authors.forename: Hui
authors.initials: H
authors.lastname: Hua
authors.forename: Ross S
authors.initials: RS
authors.lastname: Thomas
authors.forename: Antoni
authors.initials: A
authors.lastname: Hurtado
authors.forename: William
authors.initials: W
authors.lastname: Hudson
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Bayly
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Kyle
authors.forename: Manikandan
authors.initials: M
authors.lastname: Periyasamy
authors.forename: Andrew
authors.initials: A
authors.lastname: Photiou
authors.forename: Alan C
authors.initials: AC
authors.lastname: Spivey
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ortlund
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitby
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Laki
authors.initials: L
authors.lastname: Buluwela
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D056945:Hep G2 Cells; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D001141:Aromatase