Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR.
Oncotarget
; 6(13): 11150-61, 2015 May 10.
Article
en En
| MEDLINE
| ID: mdl-25883211
ABSTRACT
Triple-negative breast cancer (TNBC) does not express conventional therapeutic targets and is the only type of malignant breast cancer for which no designated FDA-approved targeted therapy is available. Although overexpression of epidermal growth factor receptor (EGFR) is frequently found in TNBC, the therapeutic effect of EGFR inhibitors in TNBC has been underwhelming. Here we show that co-treatment with clinically validated inhibitors of c-ABL (imatinib) and EGFR (lapatinib) results in synergistic growth inhibition in TNBC cells. The dual treatment leads to synergistic repression of the long non-coding RNA (lncRNA) HOTAIR (HOX Antisense Intergenic RNA). HOTAIR has been known to induce tumor growth and metastasis in breast cancer. Depleting HOTAIR alone phenocopies the dual treatment in growth suppression. We show that expression of HOTAIR is regulated by ß-catenin through a LEF1/TCF4-binding site. The dual treatment blocks nuclear expression of ß-catenin and prevents its recruitment to the HOTAIR promoter. Consistently, forced expression of ß-catenin rescued HOTAIR expression and cell viability in the presence of both drugs. Upregulation of HOTAIR is associated with TNBC in cell lines and a cohort of primary tumors. This study elucidates a previously unidentified mechanism in TNBC linking signaling with lncRNA regulation which may be exploited for therapeutic gain.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_breast_cancer
Asunto principal:
Proteínas Proto-Oncogénicas c-abl
/
Proliferación Celular
/
ARN Largo no Codificante
/
Neoplasias de la Mama Triple Negativas
/
Receptores ErbB
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Oncotarget
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos