Nrf2-dependent reprogramming of brown adipose tissue in orthotopic breast cancer model: implications for altered systemic homeostasis.

Considering cancer within the framework of systemic redox and metabolic regulation may enhance our understanding of disease progression. However, the relationship between cancer and the host redox-metabolic reprogramming within other tissues remains largely unexplored. Brown adipose tissue (BAT), as an important regulator of whole-body metabolic homeostasis, has been implicated in breast cancer progression. Here, we investigated the redox-metabolic profile of BAT and its reprogramming regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) in mice undergoing breast tumour growth. To this end, we established an orthotopic model of breast cancer in wild-type and in mice lacking functional Nrf2 (Nrf2KO) to investigate the Nrf2-driven structural, metabolic, and redox reprogramming of BAT in response to breast tumour growth (10-400 mg). Our results showed that breast tumour growth induced an early adaptive BAT response, characterised by increased uncoupling protein 1 expression. Nevertheless, in response to advanced breast tumours, BAT showed pronounced downregulation of key glycolytic and pentose phosphate pathway protein expression, particularly in Nrf2KO mice. These changes were accompanied by whitening, attenuated UCP1, decreased fatty acid synthesis protein levels, and disrupted β-oxidation protein expression in BAT from Nrf2KO mice bearing larger breast tumours. Furthermore, breast tumour growth altered the protein expression of antioxidant enzymes in BAT, with Nrf2 critical for maintaining glutathione-dependent antioxidant defence. Collectively, these findings highlight an integrative role for Nrf2 in BAT redox-metabolic homeostasis in the context of breast tumour growth, positioning it as a promising therapeutic target and advancing the understanding of breast cancer as a systemic metabolic disease.