Perioperative factors promoting cancer recurrence and metastasis are under scrutiny. While oxygen toxicity is documented in several acute circumstances, its implication in tumor evolution is poorly understood. We investigated hyperoxia long-term effects on cancer progression and some underlying mechanisms using both in vitro and in vivo models of triple negative breast cancer (TNBC). We hypothesized that high oxygen exposure, even of short duration, may have long-term effects on cancer growth. Considering that hyperoxic exposure results in reactive oxygen species (ROS) formation, increased oxidative stress and increased Brain-Derived Neurotrophic Factor (BDNF) expression, BDNF may mediate hyperoxia effects offering cancer cells a survival advantage by increased angiogenesis and epithelial mesenchymal transition (EMT). Human breast epithelial MCF10A, human MDA-MB-231 and murine 4T1 TNBC were investigated in 2D in vitro system. Cells were exposed to normoxia or hyperoxia (40%, 60%, 80% O 2 ) for 6 h. We evaluated ROS levels, cell viability and the expression of BDNF, HIF-1α, VEGF-R2, Vimentin and E-Cadherin by immunofluorescence. The in vivo model consisted of 4T1 inoculation in Balb/c mice and tumor resection 2 weeks after and 6 h exposure to normoxia or hyperoxia (40%, 80% O 2 ). We measured lung metastases and the same molecular markers, immediately and 4 weeks after surgery. The in vitro study showed that short-term hyperoxia exposure (80% O 2 ) of TNBC cells increases ROS, increases BDNF expression and that promotes EMT and angiogenesis. The in vivo data indicates that perioperative hyperoxia enhances metastatic disease and this effect could be BDNF mediated.Cancers 2020, 12, 688 2 of 18 but rather to local recurrence and metastasis. Cancer evolution after radical resection depends on many factors, mainly the stage of the disease, tumor biological features, initial therapy and immune function status [2]. During the perioperative period several events, such as surgical insult, systemic inflammation, anesthetic and analgesic drugs and blood transfusion, can favor cancer progression [3,4].Oxygen is the most common used drug in the perioperative period. General anesthesia invariably results in perioperative supplemental oxygen administration. Long-time considered as a definitely useful and harmless intervention, oxygen therapy is under scrutiny in recent years. The accumulation of data showing hyperoxia harmful effects during acute events (stroke, myocardial infarction, cardiac arrest) was followed by guidelines recommendation for oxygen use [5,6]. The optimal perioperative oxygen concentration is still poorly defined for specific circumstances. Clinical trials suggest that surgical oncological patients may have an increased risk of mortality and cancer progression when exposed to high oxygen concentration [7,8].The main mechanism of oxygen toxicity is mediated by free radical oxygen species (ROS). ROS production may be followed by increased expression of Brain-Derived Neurotrophic Factor (BDNF) [9][10][11]. BDNF ...