Abstract
Simple SummarySpecific metabolic phenotypes of breast cancer result from local interactions such as cancer-adipocyte cross-talk and systemic metabolic influences such as obesity. Here we examined key regulatory enzymes involved in glucose metabolism in breast cancer tissue and cancer-associated adipose tissue of normal-weight and overweight/obese premenopausal women in comparison to benign breast tumor tissue and adipose tissue of weight-matched women. We show a simultaneous increase in 5′-AMP-activated protein kinase (AMPK) protein expression with glucose utilization favoring glycolysis and pentose phosphate pathway in breast cancer tissue. In parallel, we show an increased AMPK protein expression with glucose utilization favoring the pentose phosphate pathway in cancer-associated adipose tissue. Moreover, specific features of cancer tissue glycolysis and glycogen metabolism differ between normal-weight and overweight/obese women. The results suggest context-dependent induction of tissue-specific Warburg effect in breast cancer and cancer-associated adipose tissue.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.
Highlights
Breast cancer incidence has been rising in recent decades [1], making it the most common malignancy among young women below 40 years of age [2]
phosphofructokinase 1 (PFK-1) showed an even higher protein expression level in malignant tumor tissues of overweight/obese women compared to malignant tumor tissue of normal-weight women, while glyceraldehyde 3-phosphate dehydrogenase (GAPDH) only showed an increased expression in malignant tumor tissues of overweight/obese women
Breast cancer tissue showed no prominent glycogen deposition played higher PFK-1 and GAPDH protein expression in overweight/obese women. These results suggest context-dependent metabolic reprogramming in breast cancer tissue and the induction of tissue-specific Warburg effect in cancer and associated adipose tissue
Summary
Breast cancer incidence has been rising in recent decades [1], making it the most common malignancy among young women below 40 years of age [2]. Despite continuous advances in diagnostic and therapeutic approaches, premenopausal breast cancer often presents at more advanced stages with worse prognoses than postmenopausal breast cancer [3,4] Another global health concern, obesity, is taking on epidemic proportions, and accumulating evidence has linked it to breast cancer incidence [5]. Most clinical studies show more aggressive breast cancer phenotypes, higher rates of metastasis, therapeutic resistance, and mortality in both pre- and postmenopausal obese women compared to normal-weight women [7,8,9]. These findings demonstrate that our current understanding of the complex relationship between breast cancer and obesity warrants urgent attention
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