The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor–Positive Breast Cancers
| Autor: | Hugo M. Horlings, Marleen Kok, Stacey E. P. Joosten, Jonna Frasor, Irida Kastrati, Svitlana D. Brovkovych, Svetlana E. Semina, Luis H. Alejo, Joshua D. Stender, Geoffrey L. Greene, Sabine C. Linn, Wilbert Zwart, Elaine T. Alarid |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Epithelial-Mesenchymal Transition Population Estrogen receptor Breast Neoplasms Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer In vivo Animals Humans Medicine Gene Regulatory Networks skin and connective tissue diseases education Molecular Biology education.field_of_study business.industry Gene Expression Profiling Estrogen Receptor alpha NF-kappa B NF-κB medicine.disease In vitro Gene Expression Regulation Neoplastic Gene expression profiling Tamoxifen 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis MCF-7 Cells Cancer research Female Neoplasm Recurrence Local business Neoplasm Transplantation hormones hormone substitutes and hormone antagonists Signal Transduction medicine.drug |
| Zdroj: | Mol Cancer Res |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | The purpose of this study was to identify critical pathways promoting survival of tamoxifen-tolerant, estrogen receptor α positive (ER+) breast cancer cells, which contribute to therapy resistance and disease recurrence. Gene expression profiling and pathway analysis were performed in ER+ breast tumors of patients before and after neoadjuvant tamoxifen treatment and demonstrated activation of the NF-κB pathway and an enrichment of epithelial-to mesenchymal transition (EMT)/stemness features. Exposure of ER+ breast cancer cell lines to tamoxifen, in vitro and in vivo, gives rise to a tamoxifen-tolerant population with similar NF-κB activity and EMT/stemness characteristics. Small-molecule inhibitors and CRISPR/Cas9 knockout were used to assess the role of the NF-κB pathway and demonstrated that survival of tamoxifen-tolerant cells requires NF-κB activity. Moreover, this pathway was essential for tumor recurrence following tamoxifen withdrawal. These findings establish that elevated NF-κB activity is observed in breast cancer cell lines under selective pressure with tamoxifen in vitro and in vivo, as well as in patient tumors treated with neoadjuvant tamoxifen therapy. This pathway is essential for survival and regrowth of tamoxifen-tolerant cells, and, as such, NF-κB inhibition offers a promising approach to prevent recurrence of ER+ tumors following tamoxifen exposure.Implications:Understanding initial changes that enable survival of tamoxifen-tolerant cells, as mediated by NF-κB pathway, may translate into therapeutic interventions to prevent resistance and relapse, which remain major causes of breast cancer lethality. |
| Databáze: | OpenAIRE |
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