RESUMEN
Triple-negative breast cancer (TNBC) exhibits a higher level of glycolytic capacity and are commonly associated with an inflammatory microenvironment, but the regulatory mechanism and metabolic crosstalk between the tumor and tumor microenvironment (TME) are largely unresolved. Here, we show that glucose transporter 3 (GLUT3) is particularly elevated in TNBC and associated with metastatic progression and poor prognosis in breast cancer patients. Expression of GLUT3 is crucial for promoting the epithelial-to-mesenchymal transition and enhancing invasiveness and distant metastasis of TNBC cells. Notably, GLUT3 is correlated with inflammatory gene expressions and is associated with M1 tumor-associated macrophages (TAMs), at least in part by C-X-C Motif Chemokine Ligand 8 (CXCL8). We found that expression of GLUT3 regulates CXCL8 production in TNBC cells. Secretion of CXCL8 participates in GLUT3-overexpressing TNBC cells-elicited activation of inflammatory TAMs, which further enhances GLUT3 expression and mobility of TNBC cells. Our findings demonstrate that aerobic glycolysis in TNBC not only promotes aggressiveness of tumor cells but also initiates a positive regulatory loop for enhancing tumor progression by modulating the inflammatory TME.
Asunto(s)
Movimiento Celular , Transportador de Glucosa de Tipo 3/metabolismo , Glucólisis , Interleucina-8/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismo , Animales , Técnicas de Cocultivo , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Transportador de Glucosa de Tipo 3/genética , Humanos , Interleucina-8/genética , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Células THP-1 , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Macrófagos Asociados a Tumores/inmunología , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The major obstacle in current cancer therapy is the existence of cancer stem cells (CSCs), which are responsible for therapeutic resistance and contribute to metastasis and recurrence. Identification of reliable biomarkers for diagnostic and therapeutic targets is necessary for drug development and cancer treatment. In this study, we identified that the antipsychotic chlorpromazine (CPZ) exhibited potent anti-breast cancer and anti-CSC capabilities. Treatment with CPZ suppressed stemness properties including mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and stemness-related gene expressions in breast cancer cells and CSCs. Moreover, CPZ increased the susceptibility of breast cancer MCF7 cells and drug-resistant MCF7/ADR cells when combined with chemotherapies. Mechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP. Elevated expression of YAP was confirmed to be crucial for stemness-related gene expressions, and was associated with invasiveness and stem-like signatures in breast cancer patients. Moreover, overexpression of YAP conferred poor outcomes particularly of basal-like breast cancer patients. Our data showed that YAP is a promising therapeutic target for breast CSCs, and CPZ has the potential to be a repurposed drug for breast cancer treatment.
