An overview of hypoxia-induced oxidative stress and NRF2 role in breast cancer progression

Despite the significant progress made in the areas of early detection, treatment, and neoadjuvant therapy, breast cancer remains a prominent cause of mortality on a global scale. The tumor microenvironment (TME) is of paramount importance in the context of therapeutic resistance and the advancement of cancer. Hypoxia, characterized by a low level of oxygen, is a prevalent attribute found in the majority of TME. Hypoxia induces the production of reactive oxygen species (ROS), leading to the occurrence of oxidative stress. The occurrence of hypoxia-induced oxidative stress results in the modification of cancer cell metabolism, impaired vascularization, enhanced cell motility, and metastasis, ultimately resulting in the acquisition of epithelial-to-mesenchymal transition (EMT). Hence, the presence of hypoxia-induced oxidative stress poses a substantial obstacle to the successful implementation of cancer therapies. Hypoxia-inducible factor-1α (HIF-1α) plays a pivotal role in the cellular response to hypoxia in tumors. It initiates the transcription of a multitude of genes, encompassing pro-angiogenic and pro-metastatic genes. Another significant signaling molecule that is activated in response to tumor hypoxia and oxidative stress is nuclear factor erythroid 2–related factor 2 (Nrf2). The regulatory role of ROS encompasses the modulation of both HIF-1α and Nrf2 signaling pathways. Moreover, the essentiality of coordinated signaling between HIF-1α and Nrf2 for tumor survival, metastasis, and chemo-resistance is evident, thereby contributing to the progression of tumors. While HIF-1α is widely recognized as a crucial mediator of the cellular reaction to low oxygen levels, it is important to note that Nrf2, a transcription factor responsible for regulating antioxidants, plays a critical role in facilitating HIF-1α-mediated responses to hypoxia. This review article places emphasis on the role of hypoxia-induced oxidative stress in the progression of breast cancer, discussing the underlying mechanisms associated with this phenomenon.