SpliceArray profiling of breast cancer reveals a novel variant of NCOR2/SMRT that is associated with tamoxifen resistance and control of ERα transcriptional activity
Menée sur des échantillons tumoraux prélevés sur 77 patientes chinoises atteintes d'un cancer du sein, cette étude identifie un nouveau variant de NCOR2 associé à la résistance au tamoxifène
Gene expression profiling aimed at classifying and prognosing breast cancer has yielded signatures with little if any concordance. However, expression arrays used in these studies do not discriminate alternate RNA splice isoforms that vary widely in cancer and might resolve this problem. In this study, we profiled splice isoforms in a panel of tamoxifen-sensitive and resistant cell lines, defining a novel variant (BQ323636.1) of the nuclear receptor co-repressor 2 (NCOR2) that was associated with tamoxifen resistance. Over-expression of this variant in a tamoxifen-sensitive cell line induced its resistance to tamoxifen. We confirmed our initial findings from cell lines in 77 breast tumors from a Chinese cohort, where BQ323636.1 expression was higher in tamoxifen-resistant patients than tamoxifen-sensitive patients. For patients who were ER-positive and had received tamoxifen treatment, higher BQ323636.1 expression level correlated with distant metastasis. High expression level of BQ323636.1 was found to be associated with poorer overall and disease-free survival for patients who had received tamoxifen treatment. Notably, higher BQ323636.1 vs. NCOR2 wild type ratio was also associated with negative ER and PR status, and triple-negative status (ER-/PR-/HER2- receptor status). Mechanistic investigations showed that under conditions of tamoxifen exposure BQ323636.1 suppressed the transcriptional activity of ERα, exhibiting promoter regulating functions. Our findings highlight a novel splice variant of the ERα co-repressor NCOR2 as a candidate biomarker in breast cancer that not only predicts tamoxifen response but might be targeted to overcome tamoxifen resistance.
Cancer Research , résumé, 2012