Breast cancer progression and metastasis are driven by complex and reciprocal 
interactions, between epithelial cancer cells and their surrounding stromal 
microenvironment. We have previously shown that a loss of stromal Cav-1 
expression is associated with an increased risk of early tumor recurrence, 
metastasis and decreased overall survival. To identify and characterize the 
signaling pathways that are activated in Cav-1 negative tumor stroma, we 
performed gene expression profiling using laser microdissected breast 
cancer-associated stroma. Tumor stroma was laser capture microdissected from 4 
cases showing high stromal Cav-1 expression and 7 cases with loss of stromal 
Cav-1. Briefly, we identified 238 gene transcripts that were upregulated and 232 
gene transcripts that were downregulated in the stroma of tumors showing a loss 
of Cav-1 expression (p ≤ 0.01 and fold-change ≥ 1.5). Gene set enrichment 
analysis (GSEA) revealed "stemness," inflammation, DNA damage, aging, oxidative 
stress, hypoxia, autophagy and mitochondrial dysfunction in the tumor stroma of 
patients lacking stromal Cav-1. Our findings are consistent with the recently 
proposed "Reverse Warburg Effect" and the "Autophagic Tumor Stroma Model of 
Cancer Metabolism." In these two complementary models, cancer cells induce 
oxidative stress in adjacent stromal cells, which then forces these stromal 
fibroblasts to undergo autophagy/mitophagy and aerobic glycolysis. This, in 
turn, produces recycled nutrients (lactate, ketones and glutamine) to feed 
anabolic cancer cells, which are undergoing oxidative mitochondrial metabolism. 
Our results are also consistent with previous biomarker studies showing that the 
increased expression of known autophagy markers (such as ATG16L and the 
cathepsins) in the tumor stroma is specifically associated with metastatic tumor 
progression and/or poor clinical outcome.