We have recently proposed a new model of cancer metabolism to explain the role 
of aerobic glycolysis and L-lactate production in fueling tumor growth and 
metastasis. In this model, cancer cells secrete hydrogen peroxide (H2O2), 
initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in 
turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted 
L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial 
cancer cells, by acting as a paracrine onco-metabolite. We have previously 
termed this type of two-compartment tumor metabolism the "Reverse Warburg 
Effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than 
epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast 
cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly 
assess the prognostic value of the "Reverse Warburg Effect." MCT4 expression is 
a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and 
L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were 
specifically associated with decreased overall survival (< 18% survival at 10 y 
post-diagnosis). In contrast, patients with absent stromal MCT4 expression 
(score = 0), had 10-y survival rates of ~97% (p-value < 10 (-32) ). High stromal 
levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 
10 (-14) ), a known marker of early tumor recurrence and metastasis. In fact, 
the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely 
identify high-risk triple-negative breast cancer patients, consistent with the 
goal of individualized risk-assessment and personalized cancer treatment. 
However, epithelial MCT4 staining had no prognostic value, indicating that the 
"conventional" Warburg effect does not predict clinical outcome. Thus, the 
"Reverse Warburg Effect" or "parasitic" energy-transfer is a key determinant of 
poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors 
should be developed for the treatment of aggressive breast cancers, and possibly 
other types of human cancers. Similarly, we discuss how stromal MCT4 could be 
used as a biomarker for identifying high-risk cancer patients that could likely 
benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such 
as, AR-C155858, AR-C117977, and AZD-3965).