OP449 inhibits breast cancer growth without adverse metabolic effects

Abstract

Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/AKT/mTOR pathway. OP449, a SET inhibitor, decreases AKT/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (<i>P</i> < 0.05), and IR phosphorylation was 4.5-fold higher in these mice (<i>P</i> < 0.05). Human and murine breast cancer tumors treated with OP449 were 47% and 39% smaller than controls (<i>P</i> < 0.05, for both, respectively). AKT and S6RP phosphorylation were 82% and 34% lower in OP449-treated tumors compared with controls (<i>P</i> < 0.05, <i>P</i> = 0.06, respectively). AKT and S6RP phosphorylation in response to insulin was 30% and 12% lower in cells, pre-treated with OP449, compared with control cells (<i>P</i> < 0.01, <i>P</i> < 0.05, respectively). However, even with decreased AKT/mTOR activation, body weights and composition, blood glucose and plasma insulin, glucose tolerance, serum triglyceride and cholesterol levels were similar between OP449-treated mice and controls. Xenografts and liver tissue from OP449-treated mice showed a 64% and 70% reduction in STAT5 activation, compared with controls (<i>P</i> < 0.01 and <i>P</i> = 0.06, respectively). Our data support an anti-neoplastic effect of OP449 on human breast cancer cells <i>in vitro</i> and in xenografts in the setting of hyperinsulinemia. OP449 led to the inhibition of AKT/mTOR signaling, albeit, not leading to metabolic derangements.