The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor–Positive Breast Cancers
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2020
- Source ID
- 10.1158/1541-7786.mcr-19-1082
Entities
People
- Elaine T Alarid
- Geoffrey L Greene
- Hugo Horlings
- Irida Kastrati
- Jonna Frasor
- Joshua D. Stender
- Luis H. Alejo
- Marleen Kok
- Sabine C. Linn
- Stacey E P Joosten
- Svetlana E Semina
- Svitlana D. Brovkovych
- Wilbert Zwart
Organizations
- National Institutes of Health
- Oncode Institute
- University of California, San Diego
- University of Chicago
- University of Illinois at Chicago
- University of Wisconsin–Madison