Abstract
Metabolic reprogramming that favors high glycolytic flux with lactate production in normoxia is among cancer hallmarks. Lactate is an essential oncometabolite regulating cellular redox homeostasis, energy substrate partitioning, and intracellular signaling. Moreover, malignant phenotype’s chief characteristics are dependent on the interaction between cancer cells and their microenvironment. In breast cancer, mammary adipocytes represent an essential cellular component of the tumor milieu. We analyzed lactate concentration, lactate dehydrogenase (LDH) activity, and isozyme pattern, and LDHA/LDHB protein expression and tissue localization in paired biopsies of breast cancer tissue and cancer-associated adipose tissue in normal-weight and overweight/obese premenopausal women, compared to benign breast tumor tissue and adipose tissue in normal-weight and overweight/obese premenopausal women. We show that higher lactate concentration in cancer tissue is concomitant with a shift in isozyme pattern towards the “muscle-type” LDH and corresponding LDHA and LDHB protein expression changes. In contrast, significantly higher LDH activity in cancer-associated adipose tissue seems to be directed towards lactate oxidation. Moreover, localization patterns of LDH isoforms varied substantially across different areas of breast cancer tissue. Invasive front of the tumor showed cell-specific protein localization of LDHA in breast cancer cells and LDHB in cancer-associated adipocytes. The results suggest a specific, lactate-centric relationship between cancer tissue and cancer-associated adipose tissue and indicate how cancer-adipose tissue cross-talk may be influenced by obesity in premenopausal women.
Highlights
Metabolic reprogramming is one of the hallmarks of breast cancer that serves to sustain the malignant phenotype in response to the selective pressures imposed by the tumor microenvironment
This study evaluated lactate metabolism in breast tumor tissue and tumor-associated adipose of normal-weight and overweight/obese premenopausal women
Cross-examination of benign and malignant tumor tissue biopsies revealed a significant shift in lactate dehydrogenase (LDH) isozyme expression towards the “muscle-type” LDH with corresponding changes in protein expression of LDHA and LDHB in malignant tumor tissue, regardless of obesity
Summary
Metabolic reprogramming is one of the hallmarks of breast cancer that serves to sustain the malignant phenotype in response to the selective pressures imposed by the tumor microenvironment. It enables progression [1], metastasis [2], and resistance to conventional therapies [3]. LDHA homotetramer, known as the “muscle-type” LDH or LDH5, preferably converts pyruvate to lactate and NAD+ and is a predominant isozyme expressed in muscle. LDHB homotetramer, called the “heart-type” LDH or LDH1, mostly converts lactate to pyruvate and NADH and is a predominant isozyme expressed in the heart. All of the above characteristics are related to cancer stemness, survival, aggressiveness, metastatic potential, and patient survival rates making lactate metabolism a potentially useful biomarker in breast cancer diagnosis, prediction, and therapy [12,16]
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