Metabolic consequences of HIF silencing in a triple negative human breast cancer xenograft

Santosh K. Bharti, Yelena Mironchik, Flonne Wildes, Marie France Penet, Eibhlin Goggins, Balaji Krishnamachary, Zaver M. Bhujwalla

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15326-15339
Number of pages14
JournalOncotarget
Volume9
Issue number20
DOIs
StatePublished - 2018

Keywords

  • Breast cancer xenografts
  • Hypoxia
  • Hypoxia inducible factor
  • MR spectroscopy
  • Metabolism

ASJC Scopus subject areas

  • Oncology

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