Molecular Portrait of Hypoxia in Breast Cancer: A Prognostic Signature and Novel HIF-Regulated Genes

Mol Cancer Res. 2018 Dec;16(12):1889-1901. doi: 10.1158/1541-7786.MCR-18-0345. Epub 2018 Jul 23.


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% O2) or hypoxic conditions (1% O2). 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Hypoxia-Inducible Factor 1 / genetics*
  • Prognosis
  • Sequence Analysis, RNA / methods*
  • Survival Analysis


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • endothelial PAS domain-containing protein 1