RESUMO
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.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/genética , Proto-Oncogenes/genética , Fatores de Transcrição SOX9/genética , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Células MCF-7 , Proteína do Locus do Complexo MDS1 e EVI1 , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Osteonectina/genética , Proteína Regulatória Associada a mTOR , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Phosphatase PRL-3 has been involved in different types of cancer, especially in metastases from colorectal carcinoma (CRC). In this study, we explored both isoforms of PRL-3 as a biomarker to predict the recurrence of stage IIIB-C CRC. Overexpression of PRL-3 was investigated in primary human colorectal tumours (n=20) and hepatic metastases (n=36) xenografted in nude mice, samples characterised by absence of human non-tumoral cells, showing a high degree of expression in metastases (P=0.001). In 27 cases of matched normal colonic mucosa/primary tumour/hepatic metastases, PRL-3 overexpression occurs in primary tumours vs normal mucosa (P=0.001) and in hepatic metastases vs primary tumours (P=0.045). Besides, our results in a series of 80 stage IIIB-C CRC primary tumours showed that high levels of PRL-3 were an independent predictor of metastasis (P<0.0001; OR: 9.791) in multivariate analysis of a binary logistic regression and that PRL-3 expression tightly correlates with parameters of bad outcome. Moreover, PRL-3 expression associated with poor outcome in univariate (P<0.0001) and multivariate Cox models (hazard ratio: 3.322, 95%, confidence interval: 1.405-7.852, P=0.006). In conclusion, PRL-3 is a good marker of aggressiveness of locally advanced CRS and a promising predictor of distant metastases. Nevertheless, for prognosis purposes, it is imperative to validate the cutoff value of PRL-3 expression in a larger and consecutive series and adjuvant setting.
