TGFß and EGF signaling orchestrates the AP-1- and p63 transcriptional regulation of breast cancer invasiveness.
Oncogene
; 39(22): 4436-4449, 2020 05.
Article
en En
| MEDLINE
| ID: mdl-32350443
ABSTRACT
Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-ß (TGFß)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGFß critically rely on epidermal growth factor receptor (EGFR) activation and expression of the ΔN isoform of transcriptional regulator p63. EGFR and ΔNp63 enabled and/or potentiated the activation of a subset of TGFß-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGFß- and EGF-induced binding of SMAD2/3 and JUNB to these gene loci was accompanied by p63-SMAD2/3 and p63-JUNB complex formation. p63 and EGFR were also found to strongly potentiate TGFß induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGFß-induced gene activation after p63 depletion. p63 is also involved in the transcriptional regulation of heparin binding (HB)-EGF and EGFR genes, thereby establishing a self-amplification loop that facilitates and empowers the pro-invasive functions of TGFß. These cooperative pro-oncogenic functions of EGFR, AP-1, p63, and TGFß were efficiently inhibited by clinically relevant chemical inhibitors. Our findings may, therefore, be of importance for therapy of patients with breast cancers with an activated EGFR-RAS-RAF pathway.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Transcripción Genética
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Neoplasias de la Mama
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Transducción de Señal
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Regulación Neoplásica de la Expresión Génica
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Factor de Transcripción AP-1
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Proteínas Supresoras de Tumor
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Factor de Crecimiento Epidérmico
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Factor de Crecimiento Transformador beta1
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Invasividad Neoplásica
Límite:
Female
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Humans
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2020
Tipo del documento:
Article
País de afiliación:
Suecia