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TBK1 expression may represent marker for tamoxifen resistance in breast cancer
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Expression of the innate immune response kinase TBK1 appears to be associated with poor response to tamoxifen treatment in patients with breast cancer, suggesting that this kinase may have a predictive and therapeutic role in breast cancer treatment, study results showed.
Researchers evaluated samples from patients with breast cancer, seeking to identify the specific role of the I-kappa-B–related kinase TBK1 in breast tumor growth. They found that TBK1-induced phosphorylation at the Ser-305 site regulated ER-alpha and tempered its transcriptional mechanism.
Ubiquitin-like domain-mutated TBK1 did not activate interferon-beta promoters, but it maintained the ability to phosphorylate ER-alpha, promote transactivation ER-alpha behavior and control the growth of breast cancer cells. Additionally, breast cancer cells were made resistant to tamoxifen in the presence of ectopic expression of TBK1.
The use of the pharmacological inhibitor BX795 in conjunction with tamoxifen stimulated tamoxifen-induced cell death in breast cancer cells and inhibited tumors. TBK1 expression was higher in patients with breast cancer and found to be positively associated with expression of ER-alpha, ER-alpha S305 and cyclin D1. In a significant finding, patients whose tumors expressed high levels of TBK1 had poor outcomes with tamoxifen treatment and demonstrated a higher likelihood of recurrence.
“Because administration of BX795 together with tamoxifen achieved a synergistic effect on tumor suppression, TBK1 might form a unique therapeutic target for overcoming both intrinsic and acquired tamoxifen resistance in breast cancers,” the researchers wrote.
Disclosure: The researchers report no relevant financial disclosures.
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