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

Abstract

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.

Application of Clinical Decision Support System to Assist Breast Cancer Patients with Lifestyle Modifications during the COVID-19 Pandemic: A Randomised Controlled Trial

“…Furthermore, the risk of BC recurrence rises in the presence of obesity [ 5 ] with negative effects on treatment efficiency [ 6 ]. One underlying mechanism that could explain the link between obesity and BC is the disrupted redox homeostasis, which is commonly present in breast and adipose tissues of BC women [ 7 ]. Weight gain after diagnosis is also usual in BC and has been associated with greater all-cause mortality rates when compared to BC women of unaltered body weight [ 8 ].…”

Oxidative Stress Linking Obesity and Cancer: Is Obesity a ‘Radical Trigger’ to Cancer?

“…As mentioned, adipose tissue dysfunction is one of the hallmarks of obesity and related metabolic disorders. Obesityinitiated oxidative stress leads to increased lipid peroxidation in adipose tissue and the formation of reactive aldehyde byproducts malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and acrolein [84,85]. It has been shown that MDA can cause frameshift mutations and substitutions in sequences rich in repetitive CG [86].…”

“…Oxidative stress, obesity-related as well as in general, has an important role in cell transformation and cancer development, with similar mechanisms determining the process (Figure 4). The transformed cells protect themselves by upregulating antioxidant enzymes and introducing metabolic adjustments to avoid cell death [17,85,93]. In fact, metabolic reprogramming is one of the prerogatives in the earlystage transition from normal to transformed cells since new demands are emerging, such as rapid proliferation [93].…”

“…With the critical oncogenes activated, protective mechanisms are propelled to limit and regulate the RONS level to the transformed cell advantage. Nrf2 is found upregulated in different types of cancer; the increased expression is considered essential to cancer cell proliferation and tumorigenesis and in correlation with tumor malignancy (Figure 4) [85,96]. DeNicola et al reported that oncogenes K-Ras, B-Raf, and Myc regulate Nrf2 transcription, thus reducing oxidative stress [97].…”

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

“…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 ].…”