Breast Cancer: Mitochondria-Centered Metabolic Alterations in Tumor and Associated Adipose Tissue.

The close cooperation between breast cancer and cancer-associated adipose tissue (CAAT) shapes the malignant phenotype, but the role of mitochondrial metabolic reprogramming and obesity in breast cancer remains undecided, especially in premenopausal women. Here, we examined mitochondrial metabolic dynamics in paired biopsies of malignant versus benign breast tumor tissue and CAAT in normal-weight and overweight/obese premenopausal women. Lower protein level of pyruvate dehydrogenase and citrate synthase in malignant tumor tissue indicated decreased carbon flux from glucose into the Krebs cycle, whereas the trend was just the opposite in malignant CAAT. Simultaneously, stimulated lipolysis in CAAT of obese women was followed by upregulated ß-oxidation, as well as fatty acid synthesis enzymes in both tumor tissue and CAAT of women with malignant tumors, corroborating their physical association. Further, protein level of electron transport chain complexes was generally increased in tumor tissue and CAAT from women with malignant tumors, respective to obesity. Preserved mitochondrial structure in malignant tumor tissue was also observed. However, mitochondrial DNA copy number and protein levels of PGC-1α were dependent on both malignancy and obesity in tumor tissue and CAAT. In conclusion, metabolic cooperation between breast cancer and CAAT in premenopausal women involves obesity-related, synchronized changes in mitochondrial metabolism.

Liver Size and its Correlation with Anthropometric Parameters and Age / El Tamaño del Hígado y su Correlación con los Parámetros Antropométricos y la Edad

SUMMARY: The liver has over 500 physiological and biochemical roles in our organism so checking of liver size and function is a part of every clinical examination. Aim of our research was to estimate liver size on computed tomography (CT) of the abdomen images and to determinate relations between liver dimensions and anthropometric parameters. The research included 99 patients, 49 men and 50 women, who were referred for CT of abdomen. We measured body height (BH) and body mass (BM), and calculated body mass index (BMI) and body surface area (BSA). Also, on CT images we measured anteroposterior (AP), laterolateral (LL) and two craniocaudal liver diameters (one at the level of midclavicular line - CCmcl, and the other was maximal - CCmax). Liver volume (LV) was calculated with formula. Our results showed that AP diameter positively correlated with BSA (r=0.30) in women. LL diameter positively correlated with BH (r=0.43), and BSA (0.31) in men. CCmcl diameter positively correlated with BH (r=0.33), BM (r=0.31), and BSA (r=0.34) in men, while in women it correlated only with BH (r=0.38). CCmax diameter positively correlated with BH (r=0.33) and BSA (r=0.33) in men. LV positively correlated with BH and BSA in both men (r=0.36, r=0.33, respectively) and women (r=0.42, r=0.31, respectively), and in men also with BM (r=0.34). LL, CCmcl, CCmax, and LV negatively correlated with aging in both sexes After the age of 60, there was a decrease in size of LL, CC diameters, as well as in LV. We concluded that liver dimensions decrease with aging, regardless of sex at the expanse of LL and CC diameters which are related to the size of body parameters, so that for a precise evaluation of liver size all three diameters should be measured, LV as well as BH, BM, and BSA.

El hígado desempeña más de 500 funciones fisiológicas y bioquímicas en nuestro organismo, por lo que comprobar el tamaño y la función de este órgano es parte de cada examen clínico. El objetivo de nuestra investigación fue estimar el tamaño del hígado mediante tomografía computarizada (TC) de imágenes del abdomen y determinar las relaciones entre las dimensiones del hígado y los parámetros antropométricos. La investigación incluyó a 99 pacientes, 49 hombres y 50 mujeres, que fueron remitidos para TC de abdomen. Medimos la altura corporal (BH) y la masa corporal (BM), y calculamos el índice de masa corporal (IMC) y el área de superficie corporal (BSA). Además, en las imágenes de TC medimos los diámetros hepáticos anteroposterior (AP), laterolateral (LL) y dos craneocaudales (uno a nivel de la línea medioclavicular - CCmcl, y el diámetro máximo - CCmax). El volumen del hígado (VI) se calculó con una fórmula. Nuestros resultados mostraron que el diámetro AP se correlacionó positivamente con BSA (r = 0,30) en mujeres. El diámetro de LL se correlacionó positivamente con BH (r=0,43) y BSA (0,31) en hombres. El diámetro CCmcl se correlacionó positivamente con BH (r=0,33), BM (r=0,31) y BSA (r=0,34) en hombres, mientras que en mujeres se correlacionó solo con BH (r=0,38). El diámetro CCmax se correlacionó positivamente con BH (r=0,33) y BSA (r=0,33) en hombres. El VI se correlacionó positivamente con BH y BSA tanto en hombres (r=0,36, r=0,33, respectivamente) como en mujeres (r=0,42, r=0,31, respectivamente), y en hombres también con BM (r=0,34). LL, CCmcl, CCmax y LV se correlacionaron negativamente con el envejecimiento en ambos sexos. Después de los 60 años, hubo una disminución en el tamaño de los diámetros LL, CC y LV. Concluimos que las dimensiones del hígado disminuyen con la edad, independientemente del sexo, en la extensión de los diámetros LL y CC que están relacionados con el tamaño de los parámetros corporales, por lo que para una evaluación precisa del tamaño del hígado se debe medir LV como BH, BM y BSA.

Second to fourth digit ratio in women with breast cancer / Relación del segundo al cuarto dígito en mujeres con cáncer de mama

SUMMARY: Digit ratio established in utero is positivelly correlated with intrauterine level of estrogen. Since the breast cancer is related to excessive and prolonged exposure to estrogen, digit ratio might be considered as useful marker in breast cancer risk assessment. The aim of the present study was to compare digit ratios in breast cancer patients and healthy controls. The study group consisted of 98 breast cancer patients aged between 29 to 84 years while the control group included 141 healthy women aged between 21 and 67 years. After collecting anamnestic data concerning menopausal status, the length of second and fourth fingers were measured and the digit ratios were calculated for both hands, as well as the difference between right and left digit ratio. Digit ratio was significantly higher on right hand in breast cancer patients compaired to healthy controls (1.003±0.05 vs. 0.990±0.03). Right digit ratio showed better predictive capacity for the breast cancer development then the left (AUC:0.609 vs. 0.541). Negative statistically significant correlation between right digit ratio and the age of breast cancer diagnosis was observed (r=-0.271). Higher values of right digit ratio in women with breast cancer when compared to healthy women suggest their higher prenatal estrogen exposure that confirms the importance of digit ratio determination in breast cancer risk assessment.

La proporción de dígitos establecida en el útero, se correlaciona positivamente con el nivel intrauterino de estrógeno. Dado que el cáncer de mama está relacionado con una exposición excesiva y prolongada a los estrógenos, la proporción de dígitos podría considerarse un marcador útil en la evaluación del riesgo de cáncer de mama. El objetivo del presente estudio fue comparar proporciones de dígitos en pacientes con cáncer de mama y controles sanos. El grupo de estudio consistió en 98 pacientes con cáncer de mama con edades comprendidas entre los 29 y los 84 años, mientras que el grupo de control incluyó a 141 mujeres sanas con edades comprendidas entre los 21 y los 67 años. Después de recopilar datos anamnésticos sobre el estado menopáusico, se midió la longitud de los dedos segundo y anular y se calcularon las proporciones de los dedos para ambas manos, así como la diferencia entre la proporción de los dedos derecho e izquierdo. La proporción de dígitos fue significativamente mayor en la mano derecha en pacientes con cáncer de mama en comparación con controles sanos (1,003 ± 0,05 frente a 0,990 ± 0,03). La proporción del dígito derecho mostró una mejor capacidad predictiva para el desarrollo de cáncer de mama que el izquierdo (AUC: 0.609 vs. 0.541). Se observó una correlación estadísticamente significativa negativa entre la proporción de dígitos derechos y la edad del diagnóstico de cáncer de mama (r=-0,271). Los valores más altos de la proporción de dígitos derechos en mujeres con cáncer de mama en comparación con mujeres sanas sugieren una mayor exposición prenatal a estrógenos que confirma la importancia de la determinación de la proporción de dígitos en la evaluación del riesgo de cáncer de mama.

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

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.

Redox profile of breast tumor and associated adipose tissue in premenopausal women - Interplay between obesity and malignancy.

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.

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

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.

Anthropometric and somatotype characteristics of women with breast cancer / Características antropométricas y somatotipos de mujeres con cáncer de mama

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.

La información en la literatura es variable sobre la relación entre el cáncer de mama, la adiposidad, el tamaño corporal y somatotipo de las mujeres. El objetivo de este estudio fue comparar las características antropométricas, la composición corporal y el somatotipo entre pacientes con cáncer de mama y controles sanos. El grupo de estudio consistió en 106 pacientes con cáncer de mama y el grupo de control de 100 mujeres sanas que se sometieron a 29 mediciones antropométricas. Las mujeres con cáncer de mama tenían mayor cantidad características antropométricas masculinas, tal como una estatura más alta (160.75±6.91 vs. 158.17±4.89 cm, p = 0.020), tronco más corto (altura sentada en premenopáusica: 84.94±5.07 vs. 88.50±3.84 cm, p = 0.001 y mujeres posmenopáusicas: 81.96±6.08 vs. 85.19±3.36 cm, p = 0.001), caderas más estrechas (29.20±3.78 vs. 32.24±1.78 cm, p = 0.000), mayor diámetro biepicondilar del húmero (premenopáusico: 6.64±0.71 vs. 6.31 ±0.42 cm, p = 0.012; posmenopáusica: 6.95±0.63 vs. 6.54±0.49 cm, p = 0.000), mayor circunferencia del antebrazo y la parte superior del muslo, bíceps inferiores y mayor grosor del pliegue de la piel del muslo. Además se observó una endomorfia significativamente menor (premenopáusica: 5.84±1.78 vs. 6.55±0.96, p = 0.027; posmenopáusica: 6.89±1.52 vs. 7.37±0.86, p = 0.035) y una ectomorfia significativamente más alta (premenopáusica: 2.05±1.30 vs. 1.41 .990.99, p = 0.018; posmenopáusica: 1.06±0.90 vs. 0.68±0.56, p = 0.007), así como una mayor mesomorfia solo en mujeres posmenopáusicas (6.10±2.04 vs. 5.37±1.34, p = 0.022). El somatotipo más representado entre las pacientes con cáncer de mama fue el endomorfomesomorfo, mientras que los controles más sanos fueron el mesomórfico endomorfo. Las características del cuerpo tipo androide aumenta el riesgo de desarrollar cáncer de mama. Los indicadores de dimensiones esqueléticas, volumen muscular y adiposidad periférica tuvieron un mejor valor predictivo sobre los marcadores de adiposidad central y general.

Somatotype characteristics of normal-weight and obese women among different metabolic subtypes.

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.

Somatotype characteristics of normal-weight and obese women among different metabolic subtypes

ABSTRACT 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.