Prognostic significance of tumor/stromal caveolin‐1 expression in breast cancer patients

Abstract

Caveolin-1 (Cav-1) has been extensively characterized in cancer biological research. However, the role of Cav-1 in the interaction between tumor and stromal cells remains unclear. In the present study, we examined Cav-1 expression in tumor cells and stromal cells in breast cancer tissue by immunohistochemical analysis and evaluated its prognostic value in a training cohort. Immunohistochemical analysis of Cav-1 expression was scored as (++), (+) or ()) according to the proportion of positively stained tumor cells (T) and stromal cells (S). Correlation analysis between tumor ⁄ stromal Cav-1 expression and clinicopathological parameters revealed that only T(++) Cav-1 status was positively associated with tumor size and histological nodal status (P = 0.019 and 0.021, respectively). Univariate analysis revealed that combined T(++) ⁄ S()) status was significantly correlated with unfavorable prognostic outcomes (P < 0.001). Multivariate analysis demonstrated that this combined status is an independent prognostic factor for primary breast cancer (P = 0.002). Clinical outcomes in different subgroups of breast cancer patients were also strictly dependent on this combined status (P < 0.05). The prognostic value of T(++) ⁄ S()) Cav-1 status was also validated in the testing cohort. Collectively, our data indicate that high Cav-1 expression in tumor cells and lack of this expression in stromal cells could help identify a particular subgroup of breast cancer patients with potentially poor survival. Further studies are required to understand the regulatory mechanism of Cav-1 in the tumor microenvironment. (Cancer Sci 2011; 102: 1590-1596

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.…”

“…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.…”

Mitochondria “fuel” breast cancer metabolism: Fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells

“…8,10 In this regard, the prognostic value of a loss of stromal caveolin-1 (Cav-1; indicative of glycolysis and autophagy in the tumor microenvironment) has now been independently validated in seven different countries, and its predictive capacity has also been extended to DCIS progression, human prostate cancers and metastatic melanoma. 8,10,[35][36][37][38][39][40][41] In addition, the expression of stromal MCT4 appears to inversely correlate with stromal Cav-1, allowing them to be used together as companion diagnostics for the detection of "two-compartment tumor metabolism." 31 However, in addition to these stromal diagnostics, new epithelial biomarkers are desperately needed to identify the corresponding onset of mitochondrial biogenesis in human breast cancer cells.…”

Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis

“…22,74,[78][79][80] Consistent with these findings, a loss of stromal Cav-1 is a powerful biomarker for a lethal tumor microenvironment, in breast and prostate cancers. 37,[81][82][83][84][85][86][87][88][89] More specifically, in breast cancer patients, a loss of stromal Cav-1 is associated with early conditions, most of the DNA damage occurs in the cancer-associated fibroblasts, as the MCF7 cancer cells effectively mount an anti-oxidant defense by upregulating key proteins, such as peroxiredoxin-1 and TIGAR.…”