Seven shades of tamoxifen resistance : Molecular mechanisms of drug resistance in breast cancer

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Title: Seven shades of tamoxifen resistance : Molecular mechanisms of drug resistance in breast cancer
Author: Hultsch, Susanne
Contributor: University of Helsinki, Faculty of Medicine, FIMM
Doctoral Programme in Biomedicin
Publisher: Helsingin yliopisto
Date: 2018-10-23
Language: en
Thesis level: Doctoral dissertation (article-based)
Abstract: Tamoxifen treatment of estrogen receptor-positive breast cancer reduces breast cancer mortality. However, resistance to tamoxifen develops frequently. A plethora of resistance mechanisms have been described but their biological importance, clinical significance, and possibilities for diagnostic or therapeutic intervention are poorly understood. Fusion genes, for example, have the potential as therapeutic targets or diagnostic tools as they are highly cancer-specific. In order to determine the mechanisms underlying endocrine therapy resistance and to identify new opportunities to defy resistance in breast cancer, we created seven tamoxifen-resistant breast cancer cell lines. We characterized the resistant cell lines by exome-sequencing to identify possible mutations or genomic rearrangements involved in drug resistance. RNA-sequencing was applied to shed light on the nature of fusion genes in the parental cell line as well as their contribution to acquired drug resistance. RNA-sequencing also exposed gene expression and pathway changes, which were followed up in detail in one of the resistant cell lines. In addition to drug sensitivity and resistance testing combined with high-content imaging, network analysis determined the drug response profiles. We further uncovered potential drug targets of tamoxifen resistance. This intensive molecular profiling revealed that each tamoxifen-resistant cell line developed its own resistance mechanism and acquired individual drug vulnerabilities. However, we were able to detect a common increased sensitivity towards an ERK1/2-inhibitor. On the other hand, we discovered co-resistance to paclitaxel, which is mostly driven by the slower growth rate of the resistant cells. Analysis of differentially expressed genes identified pathways which were associated with cell cycle, protein modification, and metabolism, especially with the cholesterol pathway. After further investigation we identified that the prevention of lysosomal membrane permeabilization was associated with drug resistance in the T-47D tamoxifen-resistant cell lines. Targeting this mechanism remains challenging. We further revealed the complex nature of fusion genes, which include the high prevalence of alternative splicing and the lack of recurrence across different breast cancer cell lines. Additionally, we identified fusion genes only present in the resistant cell lines. However, these were mainly cell clone-specific or recurrent read-through fusions. Exome-sequencing revealed no known or common mutations or copy number changes related to resistance development. With the diversity of fusion genes, mutations, copy number changes, differentially expressed genes, pathway changes, and drug responses in tamoxifen-resistant cells, it is safe to say that tamoxifen resistance cannot simply be explained by one common mechanism. Therefore, it is likely that countering the resistance will require different therapeutic approaches.Verschiedene Therapien, wie Operation, Bestrahlung, Chemo-, Targeted- und Hormontherapie, werden zur Behandlung von Brustkrebs eingesetzt. Die Überlebensraten haben sich aufgrund von neuen Therapien und verbesserter Diagnostik erhöht. Es können sich jedoch Arzneimittelresistenzen entwickeln, die oft zu einem Therapieversagen führen. Es wird angenommen, dass die Entwicklung von Arzneimittelresistenzen, die zu einem fortschreitenden Wachstum des Krebses führen, durch eine Vielzahl von Mechanismen verursacht wird. Diese Vielseitigkeit spiegelt höchstwahrscheinlich die molekularen Subtypen des Brustkrebses, sowie die spezifischen Eigenschaften einzelner Krebszellen wider. Ziel meiner Doktorarbeit war es daher, molekulare Resistenzmechanismen mit Hilfe von Tamoxifen-resistenten Zellen zu erforschen und mögliche alternative Therapieansätze zu identifizieren. Tamoxifen ist ein Arzneistoff der zur Behandlung von Östrogen-Rezeptor-positiven Brustkrebs eingesetzt wird. Intensives molekulares Profilieren zeigte, dass jede Tamoxifen-resistente Zelllinie ihren eigenen Resistenzmechanismus entwickelte. Verdeutlicht wurde dies durch die Vielfalt an Fusionsgenen, Mutationen und Chromosomveränderungen, sowie dem individuellen Wechsel der Geneexpression, der Signalwege und der Arzneimittelreaktionen in den einzelnen Tamoxifen-resistenten Zellen. Es ist daher wahrscheinlich, dass die Bekämpfung der Resistenz unterschiedliche therapeutische Ansätze erfordert.
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