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Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer

Authors Seeley TW, Sternlicht MD, Klaus SJ, Neff TB, Liu DY

Received 17 December 2016

Accepted for publication 19 January 2017

Published 10 March 2017 Volume 2017:5 Pages 1—9

DOI https://doi.org/10.2147/HP.S130526

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Dörthe Katschinski


Todd W Seeley, Mark D Sternlicht, Stephen J Klaus, Thomas B Neff, David Y Liu

Therapeutics R&D, FibroGen, Inc., San Francisco, CA, USA

Abstract: The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neundl-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592). In NeuYD mice, HIF-PHI treatments elevated erythropoiesis markers, but no differences were detected in tumor onset or the phenotypes of established tumors.

Keywords: cancer progression, erythropoiesis, hypoxia-inducible factor, hypoxia-inducible factor prolyl hydroxylase inhibitors, vascular endothelial growth factor, MMTV-Neu breast cancer model

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