The NF-κB Pathway Promotes Tamoxifen Tolerance and Disease Recurrence in Estrogen Receptor-Positive Breast Cancers.
Irida KastratiStacey E P JoostenSvetlana E SeminaLuis H AlejoSvitlana D BrovkovychJoshua D StenderHugo Mark HorlingsMarleen KokElaine T AlaridGeoffrey L GreeneSabine C LinnWilbert ZwartJonna FrasorPublished in: Molecular cancer research : MCR (2020)
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.
Keyphrases
- estrogen receptor
- breast cancer cells
- signaling pathway
- lps induced
- induced apoptosis
- pi k akt
- free survival
- gene expression
- cell cycle arrest
- nuclear factor
- small molecule
- oxidative stress
- epithelial mesenchymal transition
- crispr cas
- positive breast cancer
- stem cells
- lymph node
- inflammatory response
- physical activity
- rectal cancer
- newly diagnosed
- dna methylation
- young adults
- chronic kidney disease
- toll like receptor
- locally advanced
- immune response
- single cell
- prognostic factors
- ejection fraction
- squamous cell carcinoma
- case report
- mesenchymal stem cells
- patient reported
- childhood cancer