Abstract
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 may 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 corepressor 2 (NCOR2) that was associated with tamoxifen resistance. Overexpression 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 estrogen receptor (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 versus NCOR2 wild-type ratio was also associated with negative ER and progesterone receptor (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 corepressor NCOR2 as a candidate biomarker in breast cancer that not only predicts tamoxifen response but may be targeted to overcome tamoxifen resistance.
Highlights
Breast cancer is the most prevalent female cancer worldwide
A panel of breast cancer cell lines with differential response to tamoxifen was used in the SpliceArray profiling, as shown in Supplementary Table S1A
Eleven splice variants that were differentially expressed between tamoxifen sensitive and resistant breast cancer cell lines were selected for validation
Summary
Breast cancer is the most prevalent female cancer worldwide. About 70% of breast cancers express estrogen receptor (ER), a member of the nuclear hormone family of intracellular receptors. A selective ER modulator, is commonly used as first-line adjuvant treatment to prevent cancer recurrence for ER-positive (ERþ) breast cancers. Numerous gene expression profiling studies [5,6,7,8,9,10] have been done by different research groups with the aim of improving prognostication and classification of breast cancers, including tamoxifen responsiveness, to assist the selection of patients for the most appropriate adjuvant systemic therapies. We postulated that alternatively spliced variants may play a role in tamoxifen resistance in breast cancer and conducted custom designed splice variant profiling on a panel of breast cancer cell lines with differential response to tamoxifen treatment. A novel splice variant of the gene NCOR2 was identified that was differentially expressed between parental tamoxifensensitive and -derived resistant breast cancer cell lines. Subsequent functional studies were carried out to elucidate the underlying role of this splice variant in tamoxifen resistance
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