A novel steroid hormone receptor coactivator associated with tamoxifen resistance (#68)
Resistance to tamoxifen therapy is a major determinant of survivorship in oestrogen receptor (ERα)-positive breast cancer patients. Many patients exhibit de novo resistance, despite the presence of ERα in their tumours, whilst others who initially respond acquire resistance at a later stage. Understanding the mechanisms underlying this resistance will help in developing strategies to combat it, and aid identification of those patients most likely to relapse. Recently, the human homolog of Timeless (a Drosophila gene involved in circadian rhythm) was shown to be (i) positively correlated with increased tumour grade in breast cancer patients, (ii) a strong predictor of tamoxifen relapse and (iii) aberrantly increased in tamoxifen-resistant breast cancer cells in vitro1,2. The function of Timeless in humans is unknown, but it is clearly not involved in circadian rhythm or clock function, as it is in Drosophila.
Recently, we isolated a Timeless-encoding cDNA clone during a protein:protein interaction screen using the orphan nuclear receptor LRH-1 (NR5A2) as bait. Given recent interest in Timeless and its associations with tamoxifen resistance, we hypothesized that Timeless might act as a steroid receptor coactivator. We transfected HEK293 cells with cDNAs encoding various steroid receptors, appropriate steroid receptor-responsive reporter genes, full-length Timeless (or vector control) in the presence or absence of appropriate ligands. Timeless enhanced ligand-induced activity of ERα , AR and GR by 2-3 fold, but inhibited aldosterone-induced activity of the MR. In MCF-7 ERα-positive breast cancer cells, 17β-oestradiol treatment increased expression of the ERα target genes pS2 and c-myc by 2-3-fold, but failed to increase expression of these genes when endogenous Timeless expression was inhibited using shRNA.
Our data suggest that Timeless could represent a novel steroid hormone receptor coactivator. We are currently seeking to confirm this hypothesis, and to understand the potential involvement of Timeless in tamoxifen resistance.
- Tozlu-Kara et al (2007) Oligonucleotide microarray analysis of estrogen receptor α-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen. J Mol Endocrinol 39:305-318
- Fu et al (2011) Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk. Molecular Carcinogenesis doi:10.1002/mc.20862