The interaction between
cancer cells and their microenvironment is an important determinant of the pathological nature of
cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human
cancers forming solid
tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in
cancers is strongly associated with the poor prognoses of
cancer patients, including those with lung and breast
cancers. Multiple lines of evidence suggest that aberrantly activated NRF2 in
cancer cells drives their malignant progression and that the
cancer cells consequently develop 'NRF2 addiction.' Although the downstream effectors of NRF2 that are responsible for
cancer malignancy have been extensively studied, mechanisms of how NRF2 activation contributes to the aggressive
tumorigenesis remains to be elucidated. In this study, we found a significant correlation between NRF2 and
IL-11 status in
breast cancer patients. Based on a recent report demonstrating that
IL-11 is induced downstream of NRF2, we examined the significance of
IL-11 in NRF2-driven
tumorigenesis with a newly established NRF2 addiction
cancer model. Expression of
Il11 was elevated during the
tumorigenesis of the NRF2 addiction
cancer model, but intriguingly, it was hardly detected when the
cancer model cells were cultured in vitro. These results imply that a signal originating from the microenvironment cooperates with NRF2 to activate
Il11. To the best of our knowledge, this is the first report showing the influence of the microenvironment on the NRF2 pathway in
cancer cells and the contribution of NRF2 to the secretory phenotypes of
cancers. Disruption of
Il11 in the NRF2 addiction
cancer model remarkably inhibited the
tumorigenesis, suggesting an essential role of
IL-11 in NRF2-driven
tumorigenesis. Thus, this study suggests that
IL-11 is a potential therapeutic target for NRF2-addicted breast
cancers.