1. Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation.
- Author
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Severson TM, Nevedomskaya E, Peeters J, Kuilman T, Krijgsman O, van Rossum A, Droog M, Kim Y, Koornstra R, Beumer I, Glas AM, Peeper D, Wesseling J, Simon IM, Wessels L, Linn SC, and Zwart W
- Subjects
- Adult, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation genetics, Chemotherapy, Adjuvant, Chromatin genetics, DNA Copy Number Variations, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Female, Gene Dosage, Gene Expression Profiling methods, Hepatocyte Nuclear Factor 3-alpha genetics, Hepatocyte Nuclear Factor 3-alpha metabolism, Humans, MCF-7 Cells, Middle Aged, Netherlands, Patient Selection, Precision Medicine, Predictive Value of Tests, Protein Binding, Time Factors, Transcription, Genetic, Treatment Outcome, Breast Neoplasms drug therapy, Cell Proliferation drug effects, Chromatin metabolism, Estrogen Receptor alpha drug effects, Gene Expression Regulation, Neoplastic drug effects, Neoadjuvant Therapy, Selective Estrogen Receptor Modulators administration & dosage, Tamoxifen administration & dosage, Transcriptome drug effects
- Abstract
Estrogen receptor alpha (ERα)-positive breast cancers are frequently treated with tamoxifen, but resistance is common. It remains elusive how tamoxifen resistance occurs and predictive biomarkers for treatment outcome are needed. Because most biomarker discovery studies are performed using pre-treatment surgical resections, the effects of tamoxifen therapy directly on the tumor cell in vivo remain unexamined. In this study, we assessed DNA copy number, gene expression profiles and ERα/chromatin binding landscapes on breast tumor specimens, both before and after neoadjuvant tamoxifen treatment. We observed neoadjuvant tamoxifen treatment synchronized ERα/chromatin interactions and downstream gene expression, indicating that hormonal therapy reduces inter-tumor molecular variability. ERα-synchronized sites are associated with dynamic FOXA1 action at these sites, which is under control of growth factor signaling. Genes associated with tamoxifen-synchronized sites are capable of differentiating patients for tamoxifen benefit. Due to the direct effects of therapeutics on ERα behavior and transcriptional output, our study highlights the added value of biomarker discovery studies after neoadjuvant drug exposure., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
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