Metabolic coupling in phyllodes tumor of the breast and its association with tumor progression

Abstract

There are markers of metabolic coupling in breast cancer. Loss of caveolin-1 (Cav-1) and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, serve an important role in metabolic coupling necessary for release and uptake of metabolites. However, the occurrence of these phenomena in phyllodes tumors (PTs) of the breast is unclear. A total of 101 PTs (60 benign, 26 borderline and 15 malignant) and nine breast tissue samples with no pathological lesions were analyzed. Immunohistochemical staining for Cav-1, MCT1 and MCT4 was performed using tissue microarray and their expression in both stromal and epithelial components was assessed. Cav-1 expression in PTs demonstrated a significant decrease in the stromal component compared with that in the normal breast tissues (P<0.001). MCT1 expression in both epithelial and stromal components was significantly increased in PTs, compared with that in normal breast tissues (both P<0.001). Stromal MCT1 and MCT4 expression were different depending on tumor grade of PTs, and stromal MCT1 expression significantly increased with increasing tumor grade (P<0.001). Although not statistically significant, stromal Cav-1 expression notably decreased with increases in PT grade. High stromal MCT1 expression was significantly associated with lower disease-free survival rate in comparison with low stromal MCT1 expression (P<0.05). These results suggested that changes in protein expression of Cav-1, MCT1 and MCT4 may be associated with tumorigenesis and progression of PTs of the breast.

Keywords: caveolin-1; metabolic coupling; monocarboxylate transporter 1; monocarboxylate transporter 4; phyllodes tumor.

Figure 1.

Protein expression and localization of Cav-1, MCT1 and MCT4 was determined via immunohistochemistry in the epithelial and stromal components of normal breast tissue samples. (A) Cav-1 expression was not demonstrated in the luminal epithelial cells, but was observed in the stromal component including fibroblasts, endothelial cells and adipocytes. (B) MCT1 expression was almost exclusively confined to the epithelial component. (C) MCT4 expression was not demonstrated in epithelial or stromal components. Magnification, ×200; scale bar, 100 µm. Cav-1, caveolin-1; MCT, monocarboxylate transporter.

Figure 2.

Protein expression and localization of (A-D) Cav-1, (E-H) MCT1 and (I-L) MCT4 were determined via immunohistochemistry in the epithelial and stromal components of two benign phyllodes tumors. (A and B) High expression of Cav-1 in the stromal component. (C and D) Cav-1 expression was not demonstrated in epithelial or stromal components, except in endothelial cells. (E and F) Positive immunoreactivity of MCT1 in both epithelial and stromal components. (H and K) High MCT1 expression in the epithelial component and low expression in the stromal component. (I-L) Negative immunoreactivity of MCT4. Magnification, ×4; Scale bar, 500 µm for A, C, E, G, I and K. Magnification, ×200; Scale bar, 100 µm for B, D, F, H, J and L. Cav-1, caveolin-1; MCT, monocarboxylate transporter.

Figure 3.

Protein expression and localization of Cav-1 (A-D) MCT1 (E-H) and MCT4 (I-L) was determined via immunohistochemistry in the epithelial and stromal components of two malignant phyllodes tumors. (A and B) Immunoreactivity of Cav-1 in stromal components. (C and D) Epithelial and stromal components, excluding endothelial cells, demonstrated negative immunoreactivity of Cav-1. Strong immunoreactivity was demonstrated in endothelial cells. (E and F) Immunoreactivity of MCT1 in stromal components. (G and H) MCT1 expression is high in epithelial components, but low in stromal components. (I and J) Immunoreactivity of MCT4 in stromal components and cell membranes. (K and L) Negative immunoreactivity of MCT4. Magnification, ×4; Scale bar, 500 µm for A, C, E, G, I and K. Magnification, ×200; Scale bar, 100 µm for B, D, F, H, J and L. Cav-1, caveolin-1; MCT, monocarboxylate transporter.

Figure 4.

Prognostic analysis of stromal expression of Cav-1, MCT1 and MCT4 expression in phyllodes tumor. (A) Stromal Cav-1 expression had no prognostic value. (B) Patients with phyllodes tumor with high stromal MCT1 expression had a significantly lower disease-free survival rate. (C) Stromal MCT4 expression had no prognostic value. Cav-1, caveolin-1; MCT, monocarboxylate transporter.