Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation

// Tesa M. Severson 1 , Ekaterina Nevedomskaya 1,2 , Justine Peeters 3 , Thomas Kuilman 4 , Oscar Krijgsman 4 , Annelot van Rossum 1 , Marjolein Droog 1 , Yongsoo Kim 1,2 , Rutger Koornstra 5 , Inès Beumer 3 , Annuska M. Glas 3 , Daniel Peeper 4 , Jelle Wesseling 1 , Iris M. Simon 3 , Lodewyk Wessels 2 , Sabine C. Linn 1,6,7 and Wilbert Zwart 1 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 Correspondence to: 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 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.