Title : GPER-Driven crosstalk in breast cancer: Bridging drugs resistance and tumor microenvironment remodeling
Abstract:
Background: Triple-negative breast cancer (TNBC) is a particularly aggressive type of breast cancer, known for its lack of effective treatments and unfavorable prognosis. The G protein-coupled estrogen receptor (GPER), a novel estrogen receptor, is linked to increased malignancy in various cancers. However, its involvement in the metabolic regulation of cancer-associated fibroblasts (CAFs), a key component in the tumor microenvironment, remains largely unexplored. This study investigates how GPER influences the metabolic interaction between CAFs and TNBC cells, aiming to identify potential therapeutic targets.
Methods: The co-culture system is performed to examine the interaction between CAFs and TNBC cells, with a focus on GPER-mediated glutamine production and release by CAFs and its subsequent uptake and utilization by TNBC cells. And the definite roles of microenvironmental GPER/cAMP/PKA/CREB signaling in regulating the expression of glutamine synthetase (GLUL) and lactate dehydrogenase B (LDHB) are further investigated.
Results: Our findings reveal that estrogen-activated GPER in CAFs significantly upregulates the expression of GLUL and LDHB, leading to increased glutamine production. This glutamine is then secreted into the extracellular matrix and absorbed by TNBC cells, enhancing their viability, motility, and chemoresistance both in vitro and in vivo. TNBC cells further metabolize the glutamine through the glutamine transporter (ASCT2) and glutaminase (GLS1) axes, which in turn promotes mitochondrial activity and tumor progression.
Conclusions: The study identifies GPER as a critical mediator of metabolic coupling between CAFs and TNBC cells, primarily through glutamine metabolism. Targeting the estrogen/GPER/glutamine signaling axis in CAFs offers a promising therapeutic strategy to inhibit TNBC progression and improve patient outcomes. This novel insight into the tumor microenvironment highlights the potential of metabolic interventions in treating TNBC.
