RESUMEN
Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas de Unión al ADN/genética , Neoplasias Pulmonares/genética , Proto-Oncogenes/genética , Factor de Transcripción SOX9/genética , Serina-Treonina Quinasas TOR/genética , Factores de Transcripción/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Neoplasias de la Mama/patología , Proteínas Portadoras/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Células MCF-7 , Proteína del Locus del Complejo MDS1 y EV11 , Proteínas de Microfilamentos/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Osteonectina/genética , Proteína Reguladora Asociada a mTOR , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Chemotherapy increases survival in breast cancer patients. Consequently, cerebral metastases have recently become a significant clinical problem, with an incidence of 30-40% among breast carcinoma patients. As this phenomenon cannot be studied longitudinally in humans, models which mimic brain metastasis are needed to investigate its pathogenesis. Such models may later be used in experimental therapeutic approaches. MATERIAL AND METHODS/RESULTS: We report a model in which 69% of the animals (9/13 BALB/c nude mice) developed MR-detectable abnormal masses in the brain parenchyma within a 20 to 62-day time window post intra-carotid injection of 435-Br1 human cells. The masses detected in vivo were either single (7 animals) or multiple (2 animals). Longitudinal MR (MRI/MRS) studies and post-mortem histological data were correlated, revealing a total incidence of experimental brain metastases of 85% in the cases studied (11/13 animals). ADC maps perfectly differentiated edema and/or CSF areas from metastasis. Preliminary MRS data also revealed additional features: decrease in N-acetyl aspartate (NAA) was the first MRS-based marker of metastasis growth in the brain (micrometastasis); choline-containing compounds (Cho) rose and creatine (Cr) levels decreased as these lesions evolved, with mobile lipids and lactate also becoming visible. Furthermore, MRS pattern recognition-based analysis suggested that this approach may help to discriminate different growth stages. CONCLUSIONS: This study paves the way for further in vivo studies oriented towards detection of different tumor progression states and for improving treatment efficiency.