Nrf2 Modulation in Breast Cancer

Abstract

Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents.

Keywords: Keap1-Nrf2; Nrf2 inhibitors; antioxidant pathway; breast cancer; oxidative stress.

Figure 1

Nrf2 and ROS levels determine cell fate propensity. ROS at a higher toxicity level brings about normal cell death and tumor cell suppression, while at a lower toxicity level, it is associated with carcinogenesis and tumor progression. Conversely, high-level Nrf2 survives normal cells against ROS-related cancer progression.

Figure 2

Cytoprotective role of Keap1-Nrf2. Under high ROS levels and oxidative conditions, Nrf2 translocates to the nucleus and triggers the expression of anti-oxidant proteins.

Figure 3

Anti/Pro-carcinogenic activity of Nrf2. Under chronic oxidative conditions, various mechanisms increase cell growth and proliferation in cancer cells. Hyperactivation of Nrf2 is one of the main mechanisms that promote cancer cell proliferation and survival, and increase their resistance against chemo/radiotherapy agents.