Typical features of the breast malignant phenotype rely on metabolic reprogramming of cancer cells and their interaction with surrounding adipocytes. Obesity is strongly associated with breast cancer mortality, yet the effects of obesity on metabolic reprogramming of cancer and cancer-associated adipose tissue remain largely unknown. Paired biopsies of breast tumor tissue and adipose tissue from premenopausal women were divided according to pathohistological analyses and body mass index on normal-weight and overweight/obese with benign or malignant tumors. We investigated the protein expression of key regulatory enzymes of glycolysis, pentose phosphate pathway (PPP), and glycogen synthesis. Breast cancer tissue showed a simultaneous increase in 5′-AMP-activated protein kinase (AMPK) protein expression with typical features of the Warburg effect, including hexokinase 2 (HK 2) overexpression and its association with mitochondrial voltage-dependent anion-selective channel protein 1, associated with an overexpression of rate-limiting enzymes of glycolysis (phosphofructokinase 1—PFK-1) and pentose phosphate pathway (glucose-6-phosphate dehydrogenase—G6PDH). In parallel, cancer-associated adipose tissue showed increased AMPK protein expression with overexpression of HK 2 and G6PDH in line with increased PPP activity. Moreover, important obesity-associated differences in glucose metabolism were observed in breast cancer tissue showing prominent glycogen deposition and higher glycogen synthase kinase-3 protein expression in normal-weight women and higher PFK-1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) protein expression in overweight/obese women. In conclusion, metabolic reprogramming of glycolysis contributes to tissue-specific Warburg effect in breast cancer and cancer-associated adipose tissue.
Background: Obesity is a well known risk factor for the development of metabolic abnormalities. However, some obese people are healthy and on the other hand some people with normal weight have adverse metabolic profile, therefore it can be assumed that there is a difference in physical characteristics amongst these people. The aim of this study was to establish whether there are somatotype differences between metabolically healthy and metabolically obese women who are obese or of normal weight. Subjects and methods: Study included 230 women aged 44.76 ± 11.21y. Metabolic status was assessed according to IDF criteria, while somatotype was obtained using Heath & Carter method. Results: Significant somatotype differences were observed in the group of women with normal-weight: metabolically healthy women had significantly lower endomorphy, mesomorphy and higher ectomorphy compared to metabolically obese normal-weight women (5.84-3.97-2.21 vs. 8.69-6.47-0.65). Metabolically healthy obese women had lower values of endomorphy and mesomorphy and higher values of ectomorphy compared to 'at risk' obese women but the differences were not statistically significant (7.59-5.76-0.63 vs. 8.51-6.58-0.5). Ectomorphy was shown as an important determinant of the favorable metabolic profile (cutoff point was 0.80). Conclusion: We concluded that, in addition to fat mass, metabolic profile could be predicted by the structure of lean body mass, and in particular by body linearity. Arch Endocrinol Metab. 2016;60(1):60-5
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.
One of the underlying mechanisms that could link breast cancer and obesity is shifted redox homeostasis in the tumor microenvironment. To reveal the relationship between the malignant phenotype and obesity, we compared redox profiles of breast tumor and tumor-associated adipose tissue from premenopausal women: normal-weight with benign tumors, overweight/obese with benign tumors, normal-weight with malignant tumors, and overweight/obese with malignant tumors. Namely, we examined the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), protein expression and activity of main antioxidant defense (AD) enzymes: copper, zinc- and manganese superoxide dismutase, catalase, and glutathione peroxidase, as well as the level of 4-hydroxy-2-nonenal (4-HNE) modified proteins. Higher protein expression and activity of AD enzymes were found in malignant tumor tissue than benign tumor tissue, irrespective of obesity. Nevertheless, malignant tumor tissue of overweight/obese women was characterized by higher protein expression of Nrf2 and weaker immunopositivity for 4-HNE modified proteins. In malignant tumor-associated adipose tissue, the redox profile was clearly related to obesity. Higher Nrf2 protein expression and higher AD enzyme levels were observed in normal-weight women, while stronger immunopositivity for 4-HNE modified proteins was found in overweight/obese women. The results suggest that the complex interplay between obesity and malignancy involves redox-sensitive pathways in breast tumor and tumor-associated adipose tissue.
UDICKI, M.; ADAMOVIC, D.; SRDIC GALIC, B.; PAVLICA, T. & RADOVANOVIC, Z. Anthropometric and somatotype characteristics of women with breast cancer. Int. J. Morphol., 38(2):448-457, 2020. SUMMARY: Inconsistent data are available on the relation between breast cancer, adiposity, body size and somatotype. The aim of our study was to compare anthropometric characteristics, body composition and somatotype between breast cancer patients and healthy controls. Study group consisted of 106 breast cancer patients while control group consisted of 100 healthy women who underwent 29 anthropometric measurements. Women with breast cancer expressed more male anthropometric features like higher stature (160.75±6.91 vs. 158.17±4.89 cm, p=0.020), shorter trunk (sitting height in premenopausal: 84.94±5.07 vs. 88.50±3.84 cm, p=0.001 and postmenopausal women: 81.96±6.08 vs. 85.19±3.36 cm, p=0.001), narrower hips (29.20±3.78 vs. 32.24±1.78 cm, p=0.000), higher biepicondylar diameter of humerus (premenopausal: 6.64±0.71 vs. 6.31±0.42 cm, p=0.012; postmenopausal: 6.95±0.63 vs. 6.54±0.49 cm, p=0.000), larger upper-and forearm as well as upper thigh circumferences followed by lower biceps and higher thigh skinfold thicknesses. They also had significantly lower endomorphy (premenopausal: 5.84±1.78 vs. 6.55±0.96, p=0.027; postmenopausal: 6.89±1.52 vs. 7.37±0.86, p=0.035) and significantly higher ectomorphy (premenopausal: 2.05±1.30 vs. 1.41±0.99, p=0.018; postmenopausal: 1.06±0.90 vs. 0.68±0.56, p=0.007), as well as higher mesomorphy only in postmenopausal women (6.10±2.04 vs. 5.37±1.34, p=0.022). Most represented somatotype among breast cancer patients was endomorph-mesomorph while the most healthy controls were mesomorphic endomorph. Android body type increases the risk of development of breast cancer. Indicators of skeletal dimensions, muscle volume and peripheral adiposity had better predictive value over markers of central and overall adiposity.
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