TY - JOUR
T1 - Molecular portrait of hypoxia in breast cancer
T2 - A prognostic signature and novel HIF-regulated genes
AU - Chae Ye, I.
AU - Fertig, Elana J.
AU - DiGiacomo, Josh W.
AU - Considine, Michael
AU - Godet, Inês
AU - Gilkes, Daniele M.
N1 - Funding Information:
The authors would like to thank their funding sources for their support: Work in the Gilkes lab is supported by U54-CA210173, R00-CA181352, V Scholar Foundation, Susan G. Komen Foundation (CCR17483484), The Jayne Koskinas Ted Giovanis Foundation for Health and Policy, and the Breast Cancer Research Foundation. Work in the Fertig lab is supported by the Experimental and Computational Genomics Core (ECGC) of the Sidney Kimmel Comprehensive Cancer Center (P30CA006973). We also would like to thank João Brás, Seung Yeon Choi, Grace Kim, Jisu Shin, and Daniel Shade for support in the lab that aided in this project. We thank Dr. Ludmila Danilova for providing the TCGA data for analysis and Drs. Gregg Semenza, Ben Ho Park, and Sarawati Sukumar for careful reading and suggestions for this manuscript.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-18-0345
DO - 10.1158/1541-7786.MCR-18-0345
M3 - Article
C2 - 30037853
AN - SCOPUS:85057996179
SN - 1541-7786
VL - 16
SP - 1889
EP - 1901
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -