Molecular portrait of hypoxia in breast cancer: A prognostic signature and novel HIF-regulated genes

I. Chae Ye, Elana J. Fertig, Josh W. DiGiacomo, Michael Considine, Inês Godet, Daniele M. Gilkes

Research output: Contribution to journalArticlepeer-review

Abstract

Intratumoral hypoxia has been associated with invasion, metastasis, and treatment failure, prompting the need for a global characterization of the response to hypoxic conditions. The current study presents the results of a large-scale RNA sequencing (RNA-seq) effort, analyzing 31 breast cancer cell lines representative of breast cancer subtypes or normal mammary epithelial (NME) cells exposed to control tissue culture conditions (20% O 2 ) or hypoxic conditions (1% O 2 ). The results demonstrate that NME have a stronger response to hypoxia both in terms of number of genes induced by hypoxia as well as level of expression. A conserved 42-gene hypoxia signature shared across PAM50 subtypes and genes that are exclusively upregulated in Luminal A, Luminal B, and normal-like mammary epithelial cells is identified. The 42-gene expression signature is enriched in a subset of basal-like cell lines and tumors and differentiates survival among patients with basal-like tumors. Mechanistically, the hypoxia-inducible factors (HIF-1 and/or HIF-2) mediate the conserved hypoxic response. Also, four novel hypoxia-regulated and HIF-1–responsive genes were identified as part of the conserved signature. This dataset provides a novel resource to query transcriptional changes that occur in response to hypoxia and serves as a starting point for a clinical assay to aid in stratifying patients that would benefit from hypoxia-targeted therapies, some of which are currently in clinical trials. Implications: RNA-seq of 31 breast cancer cells exposed to control or hypoxic conditions reveals a conserved genomic signature that contains novel HIF-regulated genes and is prognostic for the survival of patients with triple-negative breast cancer.

Original languageEnglish (US)
Pages (from-to)1889-1901
Number of pages13
JournalMolecular Cancer Research
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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