Metabolic consequences of HIF silencing in a triple negative human breast cancer xenograft
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Santosh K. Bharti1, Yelena Mironchik1, Flonne Wildes1, Marie-France Penet1,2, Eibhlin Goggins1, Balaji Krishnamachary1 and Zaver M. Bhujwalla1,2,3
1Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA
2Sidney Kimmel Comprehensive Cancer Center, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA
3Department of Radiation Oncology and Molecular Radiation Sciences, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA
Zaver M. Bhujwalla, email: [email protected]
Balaji Krishnamachary, email: [email protected]
Keywords: breast cancer xenografts; hypoxia inducible factor; hypoxia; MR spectroscopy; metabolism
Received: August 25, 2017 Accepted: February 20, 2018 Epub: February 24, 2018 Published: March 16, 2018
Hypoxia is frequently encountered in tumors and results in the stabilization of hypoxia inducible factors (HIFs). These factors transcriptionally activate genes that allow cells to adapt to hypoxia. In cancers, hypoxia and HIFs have been associated with increased invasion, metastasis, and resistance to chemo and radiation therapy. Here we have characterized the metabolic consequences of silencing HIF-1α and HIF-2α singly or combined in MDA-MB-231 triple negative human breast cancer xenografts, using non-invasive proton magnetic resonance spectroscopic imaging (1H MRSI) of in vivo tumors, and high-resolution 1H MRS of tumor extracts. Tumors from all three sublines showed a significant reduction of growth rate. We identified new metabolic targets of HIF, and demonstrated the divergent consequences of silencing HIF-1α and HIF-2α individually on some of these targets. These data expand our understanding of the metabolic pathways regulated by HIFs that may provide new insights into the adaptive metabolic response of cancer cells to hypoxia. Such insights may lead to novel metabolism based therapeutic targets for triple negative breast cancer.
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