The aim of this study was to investigate the differential expression of markers related to metabolic, mitochondrial, and autophagy status in different molecular subtypes of breast cancer.

Using tissue microarray (TMA) generated with 740 cases of breast cancer, we performed immunohistochemical staining for Glut-1, CAIX, MCT4, ATP synthase, glutaminase, BNIP3, beclin-1, LC3A, LC3B, and p62. Based on the immunohistochemical expression of ER, PR, HER-2, and Ki-67 labeling index, the cases were classified into luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC). We further classified metabolic phenotypes of tumors according to glycolytic status by assessing Glut-1 and CAIX expression as follows: Warburg type: tumor (glycolysis type), stroma (non-glycolysis type); reverse Warburg type: tumor (non-glycolysis type), stroma (glycolysis type); mixed type: tumor (glycolysis type), stroma (glycolysis type); and null type: tumor (non-glycolysis type), stroma (non-glycolysis type).

Expression of Glut-1, MCT4, and LC3A was highest in TNBC and lowest in luminal A type (P < 0.001). Tumors were classified into 298 (40.3%) Warburg type, 54 (7.3%) reverse Warburg type, 62 (8.4%) mixed type, and 326 (44.0%) null type. The mixed type had a higher histologic grade, ER negativity, PR negativity, and higher Ki-67 index whereas null type showed lower histologic grade, ER positivity, PR positivity, and lower Ki-67 index (P < 0.001). TNBC constituted the major portion of Warburg and mixed type, and luminal A consisted mainly of reverse Warburg and null type (P < 0.001).

Breast cancer is heterogeneous in its metabolic status and, therefore, it can be classified into various metabolic phenotypes. Specifically, Warburg and mixed type had strong associations with TNBC whereas reverse Warburg type and null type had associations with luminal type, suggesting a correlation between metabolic phenotype and the biology of breast cancer.