Research Resource: Nuclear Receptors as Transcriptome: Discriminant and Prognostic Value in Breast Cancer

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 ER alpha(+) and ER alpha tumor tissue. In addition, we have determined NR levels in independent cohorts of tamoxifen-treated ER alpha(+) and ER alpha(-) 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 (ER alpha, EAR2, NUR77, TR alpha, and RAR gamma) 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 (TR beta, NUR77, ROR gamma, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TR beta, PPAR gamma, 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. (Molecular Endocrinology 27: 350-365, 2013)