Stromal Cell Expression of Caveolin-1 Predicts Outcome in Breast Cancer

Abstract

Caveolin-1 has been linked to tumor progression and clinical outcome in breast cancer, but a clear resolution of its role as a prognostic marker is lacking. We assessed caveolin-1 levels in normal breast tissue and two breast cancer cohorts for which outcome data were available. We found that caveolin-1 was not expressed in normal breast luminal epithelium but was present in the epithelial compartment of some tumors. We found no association between caveolin-1 expression in the epithelial compartment and clinical outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor, rather than within tumor cells, associated strongly with reduced metastasis and improved survival (P < 0.0001). The onset of mammary tumors driven by Her2/neu overexpression was accelerated in mice lacking caveolin-1, thereby supporting the observation that the presence of caveolin-1 in the tumor microenvironment modulates tumor development. These studies suggest that stromal caveolin-1 expression may be a potential therapeutic target and a valuable prognostic indicator of breast cancer progression. (Am J Pathol

Mitochondrial dysfunction in breast cancer cells prevents tumor growth

“…A loss of stromal Cav-1 and an upregulation of stromal MCT4 are markers of oxidative stress associated with poor clinical outcome in breast cancer. [34][35][36][37][38][39][40][41][42] Figure 3A and B shows that fibroblasts overexpressing UCP1, UCP2 and UCP3 all induce the downregulation of Cav-1 expression and increase MCT4 levels, as compared with control cells.…”

Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect

“…We and others have previously shown that a loss of stromal Cav-1 is associated with early tumor recurrence, metastasis, tamoxifenresistance and poor clinical outcome in human breast cancer patients. [22][23][24][25][26][27][28][29][30] Similarly, Cav-1 knock-down fibroblasts increase tumor growth, up to ~four-fold, when they are co-injected with increase in glucose uptake, as we observe in stromal fibroblasts that are co-cultured with cancer cells. Figure 12 shows that we successfully created stable Cav-1 knock-down fibroblasts, using an siRNA-based approach.…”

“…[22][23][24][25][26][27] Thus, this type of metabolism (aerobic glycolysis and autophagy in the tumor stroma) is characteristic of a lethal tumor micro-environment, as it fuels anabolic growth in cancer cells, via the production of high-energy nutrients (such as lactate, ketones and glutamine) and other chemical building blocks (fatty acids, nucleotides, amino acids). 4,11,40 Interestingly, we show here that the upstream tumor-initiating event appears to be the secretion of hydrogen peroxide by MCF7 cancer cells under co-culture conditions.…”

“…These findings may explain the prognostic value of a loss of stromal Cav-1 as a marker of a "lethal" tumor microenvironment. [22][23][24][25][26][27][28][29][30] For recent reviews on either Cav-1 or the conventional Warburg effect, please see the following references.…”

Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism

“…24,26 This has important clinical implications, as we and others have previously shown that a loss of stromal Cav-1 in human breast patients is a strong predictor of early tumor recurrence, metastasis, tamoxifen resistance and overall poor clinical outcome. [29][30][31][32][33][34][35][36][37][38][39] Similarly, elevated MCT4 in cancer-associated fibroblasts is predictive of a poor clinical outcome in breast cancer patients, and strictly correlates with a loss of Cav-1. 40 Thus, our current results with co-culture directly mirror what occurs in a specific subset of high-risk human breast cancers in patients in vivo.…”