Kalezic Andjelika, Udicki Mirjana, Srdic Galic Biljana, Aleksic Marija, Korac Aleksandra, Jankovic Aleksandra, Korac Bato
Department of Physiology, Institute for Biological Research "Sinisa Stankovic"-National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia.
Department of Anatomy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia.
Cancers (Basel). 2021 May 31;13(11):2731. doi: 10.3390/cancers13112731.
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.
乳腺恶性表型的典型特征依赖于癌细胞的代谢重编程及其与周围脂肪细胞的相互作用。肥胖与乳腺癌死亡率密切相关，然而肥胖对癌症代谢重编程及癌症相关脂肪组织的影响仍 largely 未知。根据病理组织学分析和体重指数，将绝经前女性的乳腺肿瘤组织和脂肪组织配对活检标本分为正常体重和超重/肥胖且患有良性或恶性肿瘤的组。我们研究了糖酵解、磷酸戊糖途径（PPP）和糖原合成关键调节酶的蛋白表达。乳腺癌组织显示 5'-AMP 激活蛋白激酶（AMPK）蛋白表达同时增加，伴有瓦伯格效应的典型特征，包括己糖激酶 2（HK 2）过表达及其与线粒体电压依赖性阴离子选择性通道蛋白 1 的关联，这与糖酵解限速酶（磷酸果糖激酶 1 - PFK - 1）和磷酸戊糖途径（葡萄糖 - 6 - 磷酸脱氢酶 - G6PDH）的过表达相关。同时，癌症相关脂肪组织显示 AMPK 蛋白表达增加，HK 2 和 G6PDH 过表达，这与 PPP 活性增加一致。此外，在乳腺癌组织中观察到与肥胖相关的重要糖代谢差异，正常体重女性表现为显著的糖原沉积和更高的糖原合酶激酶 - 3 蛋白表达，超重/肥胖女性表现为更高的 PFK - 1 和甘油醛 - 3 - 磷酸脱氢酶（GAPDH）蛋白表达。总之，糖酵解的代谢重编程有助于乳腺癌和癌症相关脂肪组织中的组织特异性瓦伯格效应。
