Lactate Metabolism in Breast Cancer Microenvironment: Contribution Focused on Associated Adipose Tissue and Obesity

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.

Tissue-Specific Warburg Effect in Breast Cancer and Cancer-Associated Adipose Tissue—Relationship between AMPK and Glycolysis

“…A recent in vitro study on ovarian cancer indicated a possible relationship between glycogen metabolism and cancer proliferation and metastasis, partly through stimulation of glycolysis and lactate production [ 66 ]. We recently showed that breast cancer tissues in normal-weight women have significantly higher tissue lactate concentration than those in obese women, unrelated to LDH activity and protein expression [ 25 ], which could be related to the more pronounced glycogen deposition as shown in this study. In contrast, breast cancer tissues of overweight/obese women showed higher PFK-1 and GAPDH protein expression compared to breast cancer tissues of normal-weight women.…”

“…Currently, cancer-adipose tissue cross-talk is studied as an important example of cancer-stroma metabolic cooperation [ 22 , 23 ]. Adipocytes can engage in intracellular trafficking of many metabolites, including fatty acids, glycerol, ketone bodies, lactate, as well as whole exosomes with cancer cells [ 24 , 25 ]. However, little is known about the mechanisms of adipose tissue metabolic reprogramming that enables such metabolic coupling.…”

“…Our previous studies indicated strong lactate-centric cooperation between breast cancer and cancer-associated adipose tissue in premenopausal women. Our data showed that adipose tissue-expressing lactate dehydrogenase B was found in close proximity to cancer tissue rich in lactate and expressing lactate dehydrogenase A [ 25 ]. Moreover, we showed that such complementary metabolic reprogramming was underpinned by redox reprogramming favoring increased antioxidant defense levels in both breast cancer and cancer-associated adipose tissue [ 26 ].…”

Special Issue: “Unraveling the Involvement of Adipose Tissue in Breast Cancer Progression”

“…Another possible target in adipocyte-tumor cell cross-talk is lactate dehydrogenase (LDH), a key metabolic enzyme in the conversion between pyruvate and lactate that regulates nutrient exchange between tumor and stromal cells in the tumor microenvironment, supporting tumor progression. Higher lactate production, concomitant with higher LDHA (converting pyruvate to lactate) and lower LDHB (converting lactate to pyruvate) expression in malignant BC compared with benign disease, has been observed, mainly in normal-weight patients [ 6 ]. Adipose tissue that is adjacent to tumor tissue increases LDH activity—primarily LDHB—facilitating lactate oxidation in adipocytes in stromal–epithelial metabolic coupling [ 6 ].…”

“…Higher lactate production, concomitant with higher LDHA (converting pyruvate to lactate) and lower LDHB (converting lactate to pyruvate) expression in malignant BC compared with benign disease, has been observed, mainly in normal-weight patients [ 6 ]. Adipose tissue that is adjacent to tumor tissue increases LDH activity—primarily LDHB—facilitating lactate oxidation in adipocytes in stromal–epithelial metabolic coupling [ 6 ].…”