Journal
MOLECULAR CANCER RESEARCH
Volume 16, Issue 12, Pages 1889-1901Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-18-0345
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Funding
- Susan G. Komen Foundation [CCR17483484]
- Jayne Koskinas Ted Giovanis Foundation for Health and Policy
- Breast Cancer Research Foundation
- V Scholar Foundation
- Experimental and Computational Genomics Core (ECGC) of the Sidney Kimmel Comprehensive Cancer Center [P30CA006973]
- [U54-CA210173]
- [R00-CA181352]
- NATIONAL CANCER INSTITUTE [K99CA181352, R00CA181352, P30CA006973, U54CA210173] Funding Source: NIH RePORTER
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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 th at 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. (C) 2018 AACR.
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