Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes—Obesity as a Crucial Player

SIMPLE SUMMARY: Breast cancer is a complex pathology characterized by several features including molecular subtype (MS). Immunohistochemistry assays were used to investigate the expression of enzymes involved in glycolysis and gluconeogenesis. The analysis involved stratifying the data based on MS, body mass index (BMI), and the combination of BMI with MS (mBMI). This study revealed significant differences in the expression of three specific enzymes—pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PCK), and fructose-1,6-bisphosphatase (FBP)—among tumor cells when stratified by MS and mBMI. Moreover, the expression levels of these enzymes were found to be closely related to hormonal receptor and HER2 status, as well as correlated pathological stage and histological grade. Obesity appeared to have an impact on these differences, particularly in the expression of PC. However, it was observed that these differences were not influenced by the presence of adipocyte deposition or inflammatory infiltration within the tumor microenvironment. Nevertheless, the expression of PCK and FBP was also influenced by the presence of obesity-related conditions such as diabetes, hypertension, and dyslipidemia. In summary, this study highlights the existence of distinct metabolic profiles for breast cancer based on its molecular subtypes, and how these profiles are affected by obesity and related health conditions. ABSTRACT: Breast cancer is a heterogeneous entity, where different molecular subtypes (MS) exhibit distinct prognostic and therapeutic responses. A series of 62 breast cancer samples stratified by MS was obtained from the tumor biobank of IPO-Porto. The expression of glycolysis and gluconeogenesis-regulating enzymes was investigated by immunohistochemistry. Data analysis included stratification according to MS, body mass index (BMI), and BMI with MS (mBMI). We observed significant differences in pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PCK), and fructose-1,6-bisphosphatase (FBP) tumor cell expression when stratified by MS and mBMI. The expression of these enzymes was also statistically dependent on hormonal receptors and HER2 status and correlated with pathological stage and histological grade. Obesity tended to attenuate these differences, particularly in PC expression, although these were not affected by adipocyte deposition or inflammatory infiltration at the tumor microenvironment. Nonetheless, PCK and FBP expression was also modified by the presence of obesity-associated disorders like diabetes, hypertension, and dyslipidemia. Taken together, these findings identify metabolic fingerprints for breast cancer as distinct histological types, which are affected by the presence of obesity and obesity-associated conditions. Despite the biological role of the differential expression of enzymes remaining unknown, the current study highlights the need to identify the expression of gluconeogenic-regulating enzymes as a tool for personalized medicine.