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

Tesa M Severson, Ekaterina Nevedomskaya, Justine Peeters, Thomas Kuilman, Oscar Krijgsman, Annelot van Rossum, Marjolein Droog, Yongsoo Kim, Rutger Koornstra, Inès Beumer, Annuska M Glas, Daniel Peeper, Jelle Wesseling, Iris M Simon, Lodewyk Wessels, Sabine C Linn, Wilbert Zwart

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)33901-18
Number of pages18
JournalOncotarget
Volume7
Issue number23
DOIs
Publication statusPublished - 7 Jun 2016

Cite this

Severson, T. M., Nevedomskaya, E., Peeters, J., Kuilman, T., Krijgsman, O., van Rossum, A., ... Zwart, W. (2016). Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation. Oncotarget, 7(23), 33901-18. https://doi.org/10.18632/oncotarget.8983