Severson Tesa M, Nevedomskaya Ekaterina, Peeters Justine, Kuilman Thomas, Krijgsman Oscar, van Rossum Annelot, Droog Marjolein, Kim Yongsoo, Koornstra Rutger, Beumer Inès, Glas Annuska M, Peeper Daniel, Wesseling Jelle, Simon Iris M, Wessels Lodewyk, Linn Sabine C, Zwart Wilbert
Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.
Oncotarget. 2016 Jun 7;7(23):33901-18. doi: 10.18632/oncotarget.8983.
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.
雌激素受体α（ERα）阳性乳腺癌通常采用他莫昔芬治疗，但耐药情况很常见。他莫昔芬耐药是如何发生的仍不清楚，因此需要用于预测治疗结果的生物标志物。由于大多数生物标志物发现研究是使用治疗前手术切除样本进行的，他莫昔芬治疗对体内肿瘤细胞的直接影响仍未得到研究。在本研究中，我们评估了新辅助他莫昔芬治疗前后乳腺肿瘤标本的DNA拷贝数、基因表达谱以及ERα/染色质结合图谱。我们观察到新辅助他莫昔芬治疗使ERα/染色质相互作用和下游基因表达同步，这表明激素治疗降低了肿瘤间的分子变异性。ERα同步位点与这些位点的动态FOXA1作用相关，而FOXA1作用受生长因子信号传导的控制。与他莫昔芬同步位点相关的基因能够区分出从他莫昔芬治疗中获益的患者。由于治疗对ERα行为和转录输出有直接影响，我们的研究突出了新辅助药物暴露后生物标志物发现研究的附加价值。
