Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the
G-protein-coupled
estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both
estrogen receptor (ER)-positive and -negative breast
cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in
tumor cells. However, the role of cytoplasmic GPER of CAFs on
tumor therapy remains unclear. Here we first show that the
breast tumor cell-activated PI3K/AKT (
phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel
estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs. The glycolytic CAFs feed the extra
pyruvate and
lactate to
tumor cells for augmentation of mitochondrial activity, and this energy metabolically coupled in a 'host-parasite relationship' between catabolic CAFs and anabolic
cancer cells confers the
tumor cells with multiple drug resistance to several conventional clinical treatments including endocrine
therapy (
tamoxifen), Her-2-targeted
therapy (
herceptin) and
chemotherapy (
epirubicin). Moreover, the clinical data from 18F-fluorodeoxyglucose positron emission tomography/computed tomography further present a strong association between the GPER/cAMP/PKA/CREB pathway of stromal fibroblasts with
tumor metabolic activity and clinical treatment, suggesting that targeting cytoplasmic GPER in CAFs may rescue the drug sensitivity in patients with
breast cancer. Thus, our data define novel insights into the stromal GPER-mediated multiple drug resistance from the point of reprogramming of
tumor energy metabolism and provide the rationale for CAFs as a promising target for clinical
therapy.