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OP449 inhibits breast cancer growth without adverse metabolic effects.

Publication ,  Journal Article
Shlomai, G; Zelenko, Z; Antoniou, IM; Stasinopoulos, M; Tobin-Hess, A; Vitek, MP; LeRoith, D; Gallagher, EJ
Published in: Endocr Relat Cancer
October 2017

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.

Duke Scholars

Published In

Endocr Relat Cancer

DOI

EISSN

1479-6821

Publication Date

October 2017

Volume

24

Issue

10

Start / End Page

519 / 529

Location

England

Related Subject Headings

  • Survival Analysis
  • Peptides
  • Oncology & Carcinogenesis
  • Obesity
  • Mice
  • Hyperinsulinism
  • Humans
  • Female
  • Disease Models, Animal
  • Diabetes Complications
 

Citation

APA
Chicago
ICMJE
MLA
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Shlomai, G., Zelenko, Z., Antoniou, I. M., Stasinopoulos, M., Tobin-Hess, A., Vitek, M. P., … Gallagher, E. J. (2017). OP449 inhibits breast cancer growth without adverse metabolic effects. Endocr Relat Cancer, 24(10), 519–529. https://doi.org/10.1530/ERC-17-0077
Shlomai, Gadi, Zara Zelenko, Irini Markella Antoniou, Marilyn Stasinopoulos, Aviva Tobin-Hess, Michael P. Vitek, Derek LeRoith, and Emily Jane Gallagher. “OP449 inhibits breast cancer growth without adverse metabolic effects.Endocr Relat Cancer 24, no. 10 (October 2017): 519–29. https://doi.org/10.1530/ERC-17-0077.
Shlomai G, Zelenko Z, Antoniou IM, Stasinopoulos M, Tobin-Hess A, Vitek MP, et al. OP449 inhibits breast cancer growth without adverse metabolic effects. Endocr Relat Cancer. 2017 Oct;24(10):519–29.
Shlomai, Gadi, et al. “OP449 inhibits breast cancer growth without adverse metabolic effects.Endocr Relat Cancer, vol. 24, no. 10, Oct. 2017, pp. 519–29. Pubmed, doi:10.1530/ERC-17-0077.
Shlomai G, Zelenko Z, Antoniou IM, Stasinopoulos M, Tobin-Hess A, Vitek MP, LeRoith D, Gallagher EJ. OP449 inhibits breast cancer growth without adverse metabolic effects. Endocr Relat Cancer. 2017 Oct;24(10):519–529.
Journal cover image

Published In

Endocr Relat Cancer

DOI

EISSN

1479-6821

Publication Date

October 2017

Volume

24

Issue

10

Start / End Page

519 / 529

Location

England

Related Subject Headings

  • Survival Analysis
  • Peptides
  • Oncology & Carcinogenesis
  • Obesity
  • Mice
  • Hyperinsulinism
  • Humans
  • Female
  • Disease Models, Animal
  • Diabetes Complications