title: Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.
abstract: To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERα(+) and ERα(-) tumor tissue. In addition, we have determined NR levels in independent cohorts of tamoxifen-treated ERα(+) and ERα(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors. First, there is overexpression of the NUR77 subgroup and EAR2 in neoplastic breast. Second, we identify a signature of five NR (ERα, EAR2, NUR77, TRα, and RARγ) that classifies breast samples with more than 97% cross-validated accuracy into normal or cancer classes. Third, we find a novel negative association between five NR (TRβ, NUR77, RORγ, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TRβ, PPARγ, and MR) are significant predictors of metastasis-free survival in tamoxifen-treated breast cancers, independent of ER expression. The present study highlights the discriminant and prognostic value of NR in breast cancer; identifies novel, clinically relevant, NR signatures; and highlights NR signaling pathways with potential roles in breast cancer pathophysiology and as new therapeutic targets.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia. G.Muscat@uq.edu.au
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Eriksson
authors.forename: Karen
authors.initials: K
authors.lastname: Byth
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Dinny
authors.initials: D
authors.lastname: Graham
authors.forename: Shalini
authors.initials: S
authors.lastname: Jindal
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Davis
authors.forename: Colin
authors.initials: C
authors.lastname: Clyne
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: Evan R
authors.initials: ER
authors.lastname: Simpson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ragan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kuczek
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Leedman
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clarke
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D051837:COUP Transcription Factor II / Q000378:metabolism; D044584:Carcinoma, Ductal / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D047150:Eosinophil Cationic Protein / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018776:Genes, erbA / Q000502:physiology; D006801:Humans; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis; D047495:PPAR gamma / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013534:Survival; D013629:Tamoxifen / Q000627:therapeutic use; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D051837:COUP Transcription Factor II; D047150:Eosinophil Cationic Protein; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma; D012333:RNA, Messenger; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C539821:NR4A1 protein, human; C095569:NR2F2 protein, human