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Endocr Relat Cancer. 2017 Oct;24(10):519-529. doi: 10.1530/ERC-17-0077.

OP449 inhibits breast cancer growth without adverse metabolic effects.

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Division of EndocrinologyDiabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.
The Dr Pinchas Borenstein Talpiot Medical Leadership Program 2013Tel-Hashomer, Israel.
CognosciInc., Durham, North Carolina, USA.
Department of NeurologyDuke University Medical Center, Research Drive, Durham, North Carolina, USA.
Division of EndocrinologyDiabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA


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 (P < 0.05), and IR phosphorylation was 4.5-fold higher in these mice (P < 0.05). Human and murine breast cancer tumors treated with OP449 were 47% and 39% smaller than controls (P < 0.05, for both, respectively). AKT and S6RP phosphorylation were 82% and 34% lower in OP449-treated tumors compared with controls (P < 0.05, P = 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 (P < 0.01, P < 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 (P < 0.01 and P = 0.06, respectively). Our data support an anti-neoplastic effect of OP449 on human breast cancer cells in vitro and in xenografts in the setting of hyperinsulinemia. OP449 led to the inhibition of AKT/mTOR signaling, albeit, not leading to metabolic derangements.


SET inhibition; breast cancer; hyperinsulinemia; pre-diabetes

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