Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance.
Sci China Life Sci
; 67(7): 1413-1426, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38565741
ABSTRACT
Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive (ER+) breast cancer. However, the efficacy of agents such as tamoxifen (Tam) is often compromised by the development of resistance. Here we report that cytokines-activated nuclear IKKα confers Tam resistance to ER+ breast cancer by inducing the expression of FAT10, and that the expression of FAT10 and nuclear IKKα in primary ER+ human breast cancer was correlated with lymphotoxin ß (LTB) expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam. IKKα activation or enforced FAT10 expression promotes Tam-resistance while loss of IKKα or FAT10 augments Tam sensitivity. The induction of FAT10 by IKKα is mediated by the transcription factor Pax5, and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKα attenuates p53-directed repression of FAT10. Thus, our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+ breast cancer.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Tamoxifeno
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Neoplasias de la Mama
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Transducción de Señal
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Resistencia a Antineoplásicos
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Quinasa I-kappa B
Límite:
Animals
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Female
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Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article