We and others have previously identified a loss of stromal caveolin-1 (Cav-1) in 
cancer-associated fibroblasts (CAFs) as a powerful single independent predictor 
of breast cancer patient tumor recurrence, metastasis, tamoxifen-resistance, and 
poor clinical outcome. However, it remains unknown how loss of stromal Cav-1 
mediates these effects clinically. To mechanistically address this issue, we 
have now generated a novel human tumor xenograft model. In this two-component 
system, nude mice are co-injected with i) human breast cancer cells 
(MDA-MB-231), and ii) stromal fibroblasts (wild-type (WT) versus Cav-1 (-/-) 
deficient). This allowed us to directly evaluate the effects of a Cav-1 
deficiency solely in the tumor stromal compartment. Here, we show that 
Cav-1-deficient stromal fibroblasts are sufficient to promote both tumor growth 
and angiogenesis, and to recruit Cav-1 (+) micro-vascular cells. Proteomic 
analysis of Cav-1-deficient stromal fibroblasts indicates that these cells 
upregulate the expression of glycolytic enzymes, a hallmark of aerobic 
glycolysis (the Warburg effect). Thus, Cav-1-deficient stromal fibroblasts may 
contribute towards tumor growth and angiogenesis, by providing energy-rich 
metabolites in a paracrine fashion. We have previously termed this new idea the 
"Reverse Warburg Effect". In direct support of this notion, treatment of this 
xenograft model with glycolysis inhibitors functionally blocks the positive 
effects of Cav-1-deficient stromal fibroblasts on breast cancer tumor growth. 
Thus, pharmacologically-induced metabolic restriction (via treatment with 
glycolysis inhibitors) may be a promising new therapeutic strategy for breast 
cancer patients that lack stromal Cav-1 expression. We also identify the stromal 
expression of PKM2 and LDH-B as new candidate biomarkers for the "Reverse 
Warburg Effect" or "Stromal-Epithelial Metabolic Coupling" in human breast 
cancers.