Effect of stress on growth and metastasis of breast cancer and its mechanism / 解放军医学杂志

ABSTRACT

Objective To investigate the potential mechanisms of chronic stress-induced breast cancer progression. Methods Mouse breast cancer xenograft model was established by injecting 4T1 cells into 6-week-old BALB/c mice, followed by randomized into the control group (no induced stress or drug treatment), chronic stress group, Iso injection group [10 mg/(kg.d), served as positive control], chronic stress + DMSO group (served as control for drug treatment), and chronic stress +Rapa group [15 mg/(kg.d)]. The tumor size was monitored up to 21 days. The intratumor expression levels of Beclin1, LC3-II, and p62 were detected. The pulmonary metastatic nodules were visualized and counted using lung ink staining. The expression of autophagy-related molecules in 4T1 cells after NE treatment was also examined in vitro. Results Compared with the control group [(1359.7±173.9) mm3], chronic stress [(2119.7±130.0) mm3], and Iso [(1947.0±102.8) mm3] promoted the growth of breast cancer cells (Plt;0.05). Consistently, the lung nodules numbers were significantly increased in the chronic stress group (10.3±1.1) and the Iso group (8.8±0.5), compared to control group (4.3±0.3, Plt;0.05). In addition, compared to the control group, Beclin1 expression from samples of the stress group were decreased while p62 expression increased (Plt;0.05). Interestingly, the autophagy inducer Rapa reversed the pro-tumorigenic effect of chronic stress [(2275.477±187.397) mm3 vs. (1360.097±213.938) mm3, Plt;0.05]. We further confirmed that 4T1 cells treated with NE resulted in 60% decreased of Beclin1 expression in 4T1 (100% vs. 39.8%±2.0%, Plt;0.05) the fluorescence intensity of LC3 decreased as well (Plt;0.05). Bioinformatics analysis showed that breast cancer patients with high expression of Beclin1 had better survival prognosis, while those with high expression of p62 showed worse outcome (Plt;0.001). Conclusion Stress promotes the growth and metastasis of breast cancer through suppressing cell autophagy.