Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation
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Tesa M. Severson1, Ekaterina Nevedomskaya1,2, Justine Peeters3, Thomas Kuilman4, Oscar Krijgsman4, Annelot van Rossum1, Marjolein Droog1, Yongsoo Kim1,2, Rutger Koornstra5, Inès Beumer3, Annuska M. Glas3, Daniel Peeper4, Jelle Wesseling1, Iris M. Simon3, Lodewyk Wessels2, Sabine C. Linn1,6,7 and Wilbert Zwart1
1 Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
2 Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
3 Agendia NV, Amsterdam, XH, The Netherlands
4 Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
5 Department of Medical Oncology, Radboud University Medical Center, Nijmegen, GA, The Netherlands
6 Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
7 Department of Pathology, University Medical Center Utrecht, CX, The Netherlands
Wilbert Zwart, email:
Sabine C. Linn, email:
Keywords: ChIP-seq, estrogen receptor, endocrine therapy, neoadjuvant therapy, gene expression analysis
Received: April 07, 2016 Accepted: April 13, 2016 Published: April 25, 2016
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.
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