RESUMEN
Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.
Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/genética , Interleucina-8/genética , Transcriptoma , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Interleucina-8/antagonistas & inhibidores , Interleucina-8/metabolismo , Pronóstico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Análisis de Supervivencia , Tamoxifeno/uso terapéuticoRESUMEN
With tendency to invade rapidly in the brain, malignant gliomas are very resistant to conventional therapies including radiation and chemotherapy. Recent advances in genetic and molecular techniques have made it possible to define characteristic molecular profiles of malignant gliomas. Based on the list of the molecules closely related to glioblastoma tissues, we reviewed strategies targeting them. Target molecules extensively studied include EGFR, PTEN, telomerase and signal pathway modulators for Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Therapies targeting specific molecules may result in killing tumor cells effectively while keeping normal cells intact.